Next Article in Journal
Early Life Nutrition and the Development of Offspring Metabolic Health
Next Article in Special Issue
Genomic Insights of First ermB-Positive ST338-SCCmecVT/CC59 Taiwan Clone of Community-Associated Methicillin-Resistant Staphylococcus aureus in Poland
Previous Article in Journal
Brush-like Polyaniline with Optical and Electroactive Properties at Neutral pH and High Temperature
Previous Article in Special Issue
Characterization of the Putative Acylated Cellulose Synthase Operon in Komagataeibacter xylinus E25
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Molecular Mechanisms of Drug Resistance in Staphylococcus aureus

Department of Dermatology, Immunodermatology and Venereology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
Academy of Face Sculpting, Jana Kazimierza 11B, 01-248 Warsaw, Poland
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(15), 8088;
Received: 30 June 2022 / Revised: 18 July 2022 / Accepted: 20 July 2022 / Published: 22 July 2022
(This article belongs to the Collection State-of-the-Art Molecular Microbiology in Poland)


This paper discusses the mechanisms of S. aureus drug resistance including: (1) introduction. (2) resistance to beta-lactam antibiotics, with particular emphasis on the mec genes found in the Staphylococcaceae family, the structure and occurrence of SCCmec cassettes, as well as differences in the presence of some virulence genes and its expression in major epidemiological types and clones of HA-MRSA, CA-MRSA, and LA-MRSA strains. Other mechanisms of resistance to beta-lactam antibiotics will also be discussed, such as mutations in the gdpP gene, BORSA or MODSA phenotypes, as well as resistance to ceftobiprole and ceftaroline. (3) Resistance to glycopeptides (VRSA, VISA, hVISA strains, vancomycin tolerance). (4) Resistance to oxazolidinones (mutational and enzymatic resistance to linezolid). (5) Resistance to MLS-B (macrolides, lincosamides, ketolides, and streptogramin B). (6) Aminoglycosides and spectinomicin, including resistance genes, their regulation and localization (plasmids, transposons, class I integrons, SCCmec), and types and spectrum of enzymes that inactivate aminoglycosides. (7). Fluoroquinolones (8) Tetracyclines, including the mechanisms of active protection of the drug target site and active efflux of the drug from the bacterial cell. (9) Mupirocin. (10) Fusidic acid. (11) Daptomycin. (12) Resistance to other antibiotics and chemioterapeutics (e.g., streptogramins A, quinupristin/dalfopristin, chloramphenicol, rifampicin, fosfomycin, trimethoprim) (13) Molecular epidemiology of MRSA.

1. Introduction

The species of staphylococcus that is commonly associated with increasing bacterial resistance to antibiotics is Staphylococcus aureus. It is currently included in the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), a group of the most important bacteria involved in infections and characterized by multidrug resistance [1].
S. aureus occupies a special place among the above-mentioned species due to its relatively high virulence on the one hand, and great plasticity on the other hand, enabling it to adapt to various environmental conditions. S. aureus strains have evolved resistance mechanisms to almost all antimicrobial drugs used in treatment. The most important is resistance to drugs most commonly used in the treatment of Gram-positive infections, i.e., beta-lactams, glycopeptides, and oxazolidinones.
Most problems were caused by MRSA strains, which led to infections that were difficult to treat [2]. The first MRSA strains appeared in 1960–1961 and were characterized by resistance to all the beta-lactam antibiotics then used in the treatment. It was not until 2010 that two cephalosporins, ceftobiprole and ceftaroline, active against MRSA and MRS-CN strains, were introduced. Within a short time, strains resistant to these two drugs also emerged. MRSA strains spread in the 1970s and 1980s when cephalosporins were used on a massive scale in hospitals. For many years, MRSA strains were equated with hospital-acquired MRSA (HA-MRSA, later expanded to health care-associated MRSA). Some authors use the term HCA-MRSA for this group of strains. In the 1990s, new MRSA strains started to appear, associated with infections in non-hospitalized patients (Community acquired CA-MRSA) [2] and at the beginning of the 21 st century LA-MRSA (livestock-associated MRSA) was described. Resistance to beta-lactams occurring in MRSA strains and many MRS-CN, is associated with the presence in the bacterial genome of transferable genomic islands (GI, genomic islands), called SCCmec (staphylococcal chromosomal cassette mec), where the mec gene determines resistance to methicillin. These islands evolve rapidly and contain many mobile genomic elements. Within the different types of SCCmec, there may be mecA or mecC genes and resistance genes to other groups of antibiotics such as aminoglycosides, macrolides, lincosamides, streptogramins B and tetracyclines (MLS-B) [3].
In the 90′s, strains intermediate-susceptible to vancomycin and other glycopeptides were also described (VISA—vancomycin intermediate S. aureus, GISA—glycopeptide intermediate S. aureus). According to current European EUCAST criteria, strains previously classified as VISA are now classified as VRSA (MIC vancomycin > 2 mg/L). In 2002, the first vancomycin-resistant S. aureus (VRSA) strains were detected, possessing the vanA operon in the Tn1546 transposon. Tn1546, which determines resistance to vancomycin, was described in Enterococcus genus since 1988. Subsequent studies have shown that Tn1546 is not expressed in most strains of staphylococci.
Resistance to glycopeptides encoded by the VanA operon (usually vancomycin MIC ≥ 16 mg/L) was expressed more frequently in S. aureus strains with mutation of the modification-restriction system and/or possessing the pSK41-like conjugation plasmid (factors that increase the frequency of VanA operon conjugation). Therefore, only about a dozen VRSA strains with the VanA operon have been described on the working scale [4,5,6,7].
In 2006, the first class I integrons, previously described in Gram-negative bacteria, were detected in staphylococci, initially found in coagulase-negative staphylococci and later in S. aureus. The cassette genes functioning in these integrons that determine resistance to streptomycin (aadA2, aadA5), chloramphenicol (cmlA1) and trimethoprim (dfrA12, dfr17) have also been described [8,9]. These are the same gene cassettes as found in Gram-negative bacilli. The spread of other gene cassettes and integrons in staphylococci and other Gram-positive bacteria may pose risks associated with the potential for rapid, interspecies, and intergeneric exchange of resistance genes, as well as the acquisition by Gram-positive bacteria of genes found in Gram-negative bacteria.
The efficacy of antimicrobial drugs in the treatment of S. aureus infections is not only related to the resistance or lack of resistance to a given drug, but may depend on many other factors such as the growth phase of the bacterium (logarithmic growth phase or stationary phase), the localization of the infection (drugs reach different concentrations in different compartments of the body), biofilm formation, and many others. The treatment strategy should also be correlated with the type of infection (epidemic, nosocomial, chronic, etc.), which in turn may be related to the presence or absence of a specific pathogenicity factor.
S. aureus has an enormous potential for pathogenicity. The virulence factors occur at different frequencies in different clones of bacteria. Some pathogenicity factors have several functions and can be included in several groups simultaneously. Frequently virulence genes occur together with drug resistance genes on the same genetic elements. However, the mere presence of a pathogenicity factor gene does not always equate to its expression, which is subject to one or more regulatory systems present in the bacterial cell, such as the Agr/Sar system [10] These systems can also affect the expression and stability of genes that determine antibiotic resistance.

2. Resistance to Beta-Lactam Antibiotics

Beta-lactam antibiotics target certain enzymes (transpeptidases, transglycosylases, carboxypeptidases) involved in the synthesis of peptidoglycan, a key element of the bacterial cell wall. Proteins inactivated by beta-lactams are referred to as PBPs (penicillin binding proteins). Inactivation of specific PBPs leads to bacterial cell death. Several mechanisms of resistance to beta-lactam antibiotics are known in S. aureus. These are: synthesis of a new, additional PBP called PBP2A (PBP2a, PBP2′), synthesis of beta-lactamases, and mutations in PBP genes. The mechanisms are presented in Figure 1.

2.1. Synthesis of Beta-Lactamases

In staphylococci, the mechanism involving the synthesis of beta-lactamases (penicillinases) is very common. These are enzymes with a narrow substrate spectrum, including the so-called beta-lactamase-sensitive penicillins, including natural penicillins and aminopenicillins. Beta-lactamases synthesized by S. aureus are classified as group 2a by Bush [11] and class A by Ambler. They are synthesized by most MRSA but also very frequently by MSSA. These enzymes are encoded by the blaZ gene usually within the blaI-blaR1-blaZ operon found in numerous plasmids and transposons (e.g., pI258, pII147, Tn552, Tn4002, Tn4201, SCCmec type XI) [12,13]. Four variants of staphylococcal β-lactamase (A-D) can be distinguished by serotype and currently activity profile [14]. Single strains of the so-called BORSA (borderline oxacillin-resistant S. aureus) have been described, in which the synthesized beta-lactamase had an extended spectrum and conditioned an oxacillin MIC of 4–8 mg/L [15].

2.2. PBP2A Synthesis (Methicillin-Resistance)

In S. aureus, resistance associated with the synthesis of the novel PBP2A protein is of greatest importance. Genes encoding additional PBPs are located within the SCCmec chromosomal cassettes and are transmitted by conjugation or transduction. The criterion of methicillin resistance is MIC oxacillin > 2 mg/L in S. aureus, S. lugdunensis and S. saprophyticus and MIC oxacillin > 0.25 mg/L for the remaining species of the genus Staphylococcus according to EUCAST [16] and according to CLSI for S. aureus and S. lugdunensis MIC oxacillin ≥ 4 mg/L and for the remaining species of the genus Staphylococcus MIC oxacillin ≥ 1 [17]. The cefoxitin resistance criterion is also used: MIC > 4 mg/L for S. aureus and S. lugdunensis and MIC > 8 mg/L for S. saprophyticus according to EUCAST [16] and MIC ≥ 8 mg/L for S. aureus according to CLSI [17].
Strains possessing PBP2A show resistance to all therapeutic beta-lactam antibiotics except ceftobiprole and ceftaroline and are referred to as methicillin-resistant Staphylococcus aureus, MRSA. The mechanism of methicillin resistance is closely related to PBP proteins involved in peptidoglycan synthesis. S. aureus methicillin-susceptible (MSSA) strains synthesize: PBP1 (744 amino acids, two domains: transpeptidase and dimerization), PBP2 (727 amino acids, three domains: transpeptidase, transglycosylase and carboxypeptidase), a key protein of S. aureus and inactivation of the transpeptidase function of this protein leads to cell death, PBP3 (691 amino acids, two transpeptidase and dimerization domains) and PBP4 (491 amino acids, D-alanyl-D-alanine carboxypeptidase domain) [18]. MRSA strains additionally synthesize PBP2A (PBP2a or PBP2′) of 668 amino acids, which replaces the transpeptidase function of PBP2 and takes over the transpeptidase function of other, inactivated PBPs. Beta-lactam antibiotics inactivate the PBP2 transpeptidase domain, while the PBP2 transglycosylase domain remains active and, in the case of MRSA strains, cooperates with the PBP2A transpeptidase [19]. PBP2A, together with about 40 other enzymes, is involved in the formation of pentaglycan bridges, between L-lysine (position 3 of the pentapeptide) of one chain and D-alanine (position 4 of the pentapeptide) of the other peptidoglycan chain. This enables the synthesis of the cell wall. PBP2A expression can be inducible or constitutive. PBP2A synthesis is usually associated with the presence mecI-mecR1-mecA or mecIc-mecR1c-mecC operon (inducible expression) or ΔmecR1-mecA (constitutive expression), located in staphylococcal chromosomal cassette mec (SCCmec) cassettes, found in the chromosome and classified as so-called genomic islands (GI) [20]. The mec genes are transferred to susceptible strains together with the entire SCCmec structure.
In bacteria belonging to the Staphylococcaceae family, 8 genes encoding the PBP2a transpeptidase have been described. The mecA gene has been detected in S. aureus, S. pseudintermedius, Mammallicoccus fleuretti (former name Staphylococcus fleuretti), Mammallicoccus vitulinus (former name Staphylococcus vitulinus), Mammallicoccus sciuri (former name Staphylococcus sciuri) and in many other species of the genus Staphylococcus currently comprising 64 species [21]. The mecA1 gene has been described in M. sciuri. It is considered a precursor of the mecA gene in S. aureus, and the mecA2 gene. M. sciuri oxacillin-susceptible (OS-MRSS, MIC oxacillin = 1 mg/L; according to current criteria, these are methicillin-resistant strains) and MRSS strains were described (they had two genes: mecA1 and mecA) [22]. The mecA2 gene was described in M. vitulinus and S. capitis, the mecB gene in Macrococcus caseolyticus and S. aureus, the mecC gene in S. aureus and M. sciuri, the mecC1 gene in S. xylosus, the mecC2 gene in S. saprophyticus, and the mecD gene in M. caseolyticus [23,24]. Evolutionarily, the mecA gene present in S. aureus is likely derived from the coagulase-negative staphylococcal group S. sciuri which includes S. sciuri, S. fleurettii, S. vitulinus, among others [24]. In 2018, the expression of mecB and mecD genes previously described in Macrococcus caseolyticus isolated from dogs and cattle were described in S. aureus [25]. The mecB gene was described to be present in plasmid pSAWWU4229 1 of 84599 bp. This plasmid also encoded resistance genes to aminoglycosides, macrolides and tetracyclines. [25].

SCCmec Chromosomal Cassettes

Fourteen major types of SCCmec have been described and sequenced, and within the major types are several subtypes [26,27,28,29,30,31,32]. The described SCCmec’s range in size from 21 to 82 thousand nucleotides. In the structure of SCCmec cassettes, five regions are usually specified. The orfX included in the schematic is a site in the chromosome into which SCCmec is incorporated by unauthorized recombination and is not part of SCCmec (Figure 2).
The division of SCCmec into main types is related to the type of ccr chromosomal recombinase gene complex: ccrA, ccrB, ccrC. Within ccrA we distinguish ccrA1, ccrA2, ccrA3 and ccrA4 which are found in S. aureus. ccrA1 has also been described in S. hominis and S. saprophyticus, ccrA4 has been described in S. epidermidis, in addition ccrA5 has been described in S. pseudintermedium and ccrA7 has been described in S. sciuri. Within ccrB there are ccrB1, ccrB2, ccrB3, ccrB4, and ccrB6 which are found in S. aureus. ccrB1 is described in S. hominis, ccrB3 is described in S. pseudintermedius, ccrB4 is described in S. epidermidis, and ccrB6 and ccrB7 are described in S. saprophyticus. Among ccrC1, allotypes have been described, with 1, 2, 3, 4, and 8 found in S. aureus, 5 and 6 described in S. haemolyticus, allotype 7 described in S. epidermidis, and allotype 9 described in S. saprophyticus [33,34,35].
The second important criterion for the division of SCCmec is the class of the mec region. The following classes are distinguished: A, B, B2, C1, C2, D, and E. The different classes differ in the degree of deletion of mecI-mecR (ΔmecR1), regulatory genes and their proximity and distance from the complete or reduced (Δ,Ψ) insertion sequences IS431, IS1182 and IS1272 [32,33,34,36]. The division of SCCmec into subtypes is based on the mec region subclasses and the structure of the J1, J2, and J3 regions [32,37,38].
Complexes of gene mec and ccr [33,34,38] are shown in Table 1 and Table 2.
In S. pseudintermedius, ccrA5 and ccrB3 (ccr gene complex 6) were described in SCCmec KM241 and ccrC6 in SCCmec NA45 [41]. ccrA1 and ccrB4 were described in S. saprophyticus and ccrA5/ccrB3 in S. hominis, S. haemolyticus and S. cohnii; ccrA1/ccrB1 and ccrC1 in S. cohnii, ccrA2/ccrB2 and ccrC1 and ccrA4/ccrB4 and ccrC1 in S. epidermidis and ccrA7/ccrB3 in M. sciuri [42].
The types of SCCmec chromosomal cassettes found in different MRSA clones according to [26,43,44,45,46,47,48,49,50,51,52] are shown in Table 3.
Multiple SCCmec subtypes have been described (strain-GenBank accession No.): IIa (N315, Mu50, MRSA252, JH1-NC_002745, NC_002758, BX571856, NC_009632); IIb (JCSC3063-AB127982); IIc (AR13.1.3330. 2-AJ810120); IId (RN7170-AB261975), IIe (JCSC6833-AB435013) [32,37,43,53,54,55,56]; IIIA (HU25-AF422651, AF422696); IIIB (HDG2) [30,37]; IVa (CA05-AB063172); IVb (8/6-3P-AB063173); IVc (MR108, MRSA NN424-AB096217, KX211998. 1); IVd (JCSC4469-AB097677); IVE (AR43/3330. 1-AJ810121.1); IVF; IVg (M03-68-DQ106887); IVh (HO50960412/EMRSA15-HE681097); IVi (JCSC6668/CCUG41764 -AB425823); IVj (JCSC6670/CCUG27050-AB425824); IVk (45394F-GU122149); IVl (NN50, SI1-AB633329. 1, LC425379.1); IVm (JCSC8843-AB872254); IVn (ST93-KX385846. 1); IVo [28,32,37,57,58,59,60,61,62,63,64,65,66]; Va (WIS(WBG8318)-AB121219); Vb (TSGH17, JCSC7190), PM1, JCSC5952-AB512767, AB462393, AB478780); Vc (S0385, JCSC6944-AM990992, AB505629) [26,45,52,67].

2.3. Mutation-Dependent Modification of PBP Proteins

Mutations in genes encoding PBP2 and PBP4 causing oxacillin resistance are very rare and strains are described as MODSA (modified penicillin-binding protein S. aureus) or MRLM (methicillin-resistant lacking mec). The most frequent causes are mutations in the promoter region of the pbp4 gene and in the gdpP (phosphodiesterase c-di-AMP regulator) and yjbH (disulfide stress effector) genes, conditioning the overproduction of PBP4 protein [68,69,70]. Resistance to ceftobiprole was described in S. aureus strain CRB (a derivative of strain COL). The strain lacked the mecA gene, but had substitution in PBP4 protein (E183A, F241R), GdpP signaling protein (N182K) and the ArcB/D/F cations efflux pump protein (I960V). The presence of the above-mentioned mutations resulted in CRB strain resistance to beta-lactam antibiotics: ceftobiprole (MIC = 128 mg/L), ceftriaxone (MIC = 256 mg/L), cefazolin (MIC > 256 mg/L), nafcillin (MIC = 128 mg/L), ampicillin (MIC = 256 mg/L). Only the MIC of cefoxitin was relatively low (8 mg/L) [71]. Substitutions in PBP4 protein (N138K or I, R200L, T201A, F241L, and H270L) determining resistance to ceftobiprole and ceftaroline in MSSA strains were also described [72]. In MRSA strains, resistance to ceftobiprole and ceftaroline is caused by mutations in the mecA gene. Strains harboring a D239L, S225R, N146K substitution or a 259–260 insertion in PBP2A had ceftobiprole MICs of 4–8 mg/L [73,74]. Amino acid substitutions in the PBP2A protein such as L357I, E447K, I563T, and S649A in the BND (penicillin-binding domain) and substitutions N104K, V117I, N146K and A228V located outside the BND have also been shown to be responsible for ceftaroline resistance in MRSA strains [75,76]. Breakpoint of resistance to ceftaroline is MIC > 1 mg/L (pneumonia) and MIC > 2 mg/L (other than pneumonia) according to EUCAST [14] and MIC ≥ 8 mg/L according to CLSI [17]. Breakpoint of ceftobibrole resistance is reported only by EUCAST (MIC > 2 mg/L) [16].

3. Resistance to Glycopeptides and Lipoglycopeptides

Glycopeptides and lipoglycopeptides, like beta-lactams, are bactericidal and their mechanism of action is through inhibition of peptidoglycan synthesis, but their target and exact mechanism of action is quite different. Glycopeptides and lipoglycopeptides form bonds with the dipeptide D-Ala-D-Ala within GlcNAc-β-(1,4)-MurNAc-pentapetide, the precursor of peptidoglycan. Oritavancin also shows affinity for binding to the D-ala-lactate dimer within GlcNAc-β-(1,4)-MurNAc-pentapetide found in strains expressing the VanA operon. These processes occur outside the cytoplasmic membrane. Moreover, lipoglycopeptides bind to the bacterial cytoplasmic membrane and cause rapid, concentration-dependent depolarization of the cytoplasmic membrane, increased permeability and leakage of cellular ATP and K+ ions leading to cell death. Moreover, lipoglycopeptides probably inhibit transglycosidases which are involved in the polymerization of uncrosslinked peptidoglycan precursors [77].
The criteria for S. aureus resistance to glycopeptides used in Europe (EUCAST) and in the USA (CLSI) differ significantly. According to EUCAST, S. aureus resistant to vancomycin (VRSA) or teicoplanin (TRSA) have MIC > 2 mg/L [16] and according to CLSI breakpoint for VRSA is MIC ≥ 16 mg/L and for TRSA is MIC ≥ 32 mg/L [17]. Breakpoints of resistance to lipoglycopeptides such as dalbavancin, oritavancin and telavancin are MIC > 0.125 mg/L according to EUCAST [16]. CLSI reports only breakpoint sensitivity, MIC ≤ 0.12 mg/L for oritavancin and telavancin and MIC ≤ 0.25 mg/L for dalbavancin [17].
Resistance to glycopeptides has been best described in enterococci. It can be conditioned by different operons named after the ligase they encode: VanA, VanB, VanC, VanD, VanE, VanG, VanL, VanM and VanN. In S. aureus, resistance to high concentrations of glycopeptides occurs very rarely and is then conditioned by the VanA operon derived from Enterococcus spp (Figure 1). It consists, as in Enterococcus spp., in the synthesis of an altered precursor of the cell wall, which instead of the terminal group D-Ala-D-Ala has D-Ala-D-lactate [78].
The VanA operon that determines resistance to vancomycin (MIC 64–1024 mg/L) and teicoplanin (MIC 16–512 mg/L) is composed of 7 genes, (vanRASAHAAXAYAZA) (Figure 3) located at Tn1546 and was described in E. faecalis, E. faecium, E. gallinarum, E. casseliflavus, E. avium, E. durans, E. mundtii and E. rafinosus [76]). The Van A operon shows inducible expression mediated by two regulatory genes vanRA (regulator) and vanSA (sensor, a signal histidine kinase located in the cytoplasmic membrane). vVanSA sensor activation is caused by both vancomycin and teicoplanin. Alterations in the central vanRSHA region of the Tn1546 transposon can result in varying teicoplanin MICs from >256 to <4 mg/L [79].
VRSA conditioned by the VanA operon emerged in the US in 2002 and resulted from the transfer of Enterococcus spp. Tn1546 was incorporated into a plasmid and into MRSA strains. Single VRSA or VRSA/TRSA strains have been described in the USA and Asia [4,5]. The first VRSA, Michigan (MI-VRSA) had high resistance to vancomycin and teicoplanin and a 57.9 kb plasmid, similar to pSK41, with a Tn1546-like insertion [5], while the one originating from Pennsylvania (PE-VRSA) showed resistance only to vancomycin and easily lost the plasmid with the VanA operon [80]. MRSA strains with a VanA operon that was not expressed were also detected, which are difficult to detect by routine diagnostics [81]. Most VRSA strains have been found to belong to the common MLST (multilocus sequence typing) CC5 clonal complex [6,7]. In addition, some VRSA with the VanA operon had a mutation in the hsdR gene encoding Sau1 (1 modification-restriction system) [5]. In several S. aureus strains carrying the vanA gene (irrespective of its expression), the presence of other resistance genes probably derived from E. faecium: ermB (MLS-B resistance), aadE(ant(6)-Ia) (streptomycin resistance), sat4 (streptothricin resistance), aphA-3 (Aph(3′)-IIIa, aminoglycosides resistance), msrA (efflux macrolides and streptogramins B), aac(6′)-aph(2″)-Ia (resistance to aminoglycosides), and tet(S) and tet(U), (resistance to tetracyclines) [82]. The 57.9 kb conjugative plasmid pLW043 (GenBank AE017171) described in S. aureus contained, among other things, the VanA operon in the Tn1546 transposon, the beta-lactamase operon, the aac(6′)/aph(2″) gene for bifunctional aminoglycoside transferase, and the dfrA gene for dihydrofolate reductase that determines resistance to trimethoprim [82].
In addition to VRSA (GISA) strains, the 2022 CLSI criteria specify VISA (MIC vancomycin 4–8 mg/L) and hVISA (heterogeneous VISA) strains. The vancomycin MIC for hVISA strains is usually 1.5–3 mg/L and hVISA qualification requires confirmation by population PAP-AUC analysis. The PAP-AUC ratio was interpreted as follows, <0.9 as vancomycin-susceptible S. aureus (VSSA), ≥0.9 as hVISA phenotype, >1.3 as vancomycin-intermediate S. aureus (VISA) [83].
The reduced sensitivity to vancomycin is probably due to different genome rearrangements. According to the 2022 EUCAST criteria [16] currently in force in Europe, we designate S. aureus strains as vancomycin resistant (MIC > 2 mg/L) or sensitive (MIC2 mg/L). Sensitivity to vancomycin according to EUCAST is equivalent to the sensitivity to lipoglycopeptides: dalbavancin, oritavancin and telavancin (MIC ≤ 0.125 mg/L).
VISA strains (VRSA according to EUCAST criteria) were mostly described within HA-MRSA clones such as ST5-II/III, ST8-II, ST239-III, ST241-III, ST247-IA. VISA was also described in ST1-IV, ST30-IV, ST59-IV, ST72-IV, ST81-IV, ST45, ST228-I, ST398, ST900-III, ST1301-II [84,85,86,87]. Substitutions in VraS (S329L), MsrR (E146K), GraR (N197S), RpoB (H481Y or N), Fdh2 (A297V) proteins have been shown to be closely related to vancomycin resistance of VISA strains [88]. The accumulation of mutations in genes encoding binary regulatory systems such as WalKR (sensor protein kinase/regulator), GraSR (glycopeptide resistance-associated sensor/regulator), and VraSR (vancomycin resistance associated sensor/regulator) plays a major role in the formation of hVISA/VISA strains [75].
S. aureus TRSA strains sensitive to vancomycin (MIC 1.5–3 mg/L) and resistant to teicoplanin (MIC 4–32 mg/L) were also described. S. aureus strains are defined as resistant according to EUCAST criteria (MIC > 2 mg/L) [16] and according to CLSI criteria (MIC ≥ 32 mg/L) [17]. These were methicillin-resistant strains belonging to ST772-V, ST672-IVa and ST22-IVc. The resistance was probably caused by mutations in tcaA (sibstitutions in TcaA D230E or F290S), tcaB (substitution in TcaB Y6R), lytS (LytS substitutions: P315R, A318Q, A319L, I320S, andV321M), and rhoR (substitutions in RhoR: V186I, L144I and V535M) genes [84].
An S. aureus strain V036-V64 (ST5) with a MIC of 64 mg/L vancomycin obtained from a susceptible strain by multiple passages on vancomycin medium was also described. Single amino acid substitutions in 8 proteins were shown relative to the starting strain:
RimM (G16D), SsaA2 (G128A), RpsK (P60R), RpoB (R917C), WalK (T492R), D-alanyl-D-alanine carboxypeptidase (L307I), VraT (A152V), and chromosome segregation ATPase (T440I). Strain V036-V64 showed an increase in the MIC of vancomycin from 0.5 to 64 mg/L, teicoplanin from 0.5 to 3 mg/L, daptomycin from 0.25 to 4 mg/L, and telavancin from 0.047 to 0.25 mg/L (telavancin resistance according to EUCAST) [89].
In S. aureus there is also a phenomenon of tolerance to glycopeptides (MBC/MIC32). Such strains show sensitivity to glycopeptides but are not killed by them. Picazo et al. [90] studied the phenomenon of tolerance to vancomycin and teicoplanin in 187 MRSA strains from 41 Spanish hospitals and showed tolerance to vancomycin in 9.6% of MRSA strains and tolerance to teicoplanin in 21.9% of MRSA strains [90]. The reason for vancomycin tolerance may be the ability to form a biofilm and, in non-biofilm-forming strains, altered autolysis activity, by lysogenic conversion, for example [91,92].

4. Resistance to Oxazolidinones

Linezolid and tedizolid belong to oxazolidinones and act on the 23S rRNA molecule in the 50S subunit of the ribosome (inhibition of protein synthesis) and show high activity against S. aureus (including MSSA, MRSA, VRSA and VISA). Linezolid binds to the conserved nucleotide A2602, which is part of the V domain of the 23S rRNA in the 50S subunit, and to two proteins on the same subunit: the ribosomal protein L27, whose N-end is closely adjacent to the active center of peptidyl transferase, and the LepA [93].
S. aureus strains for which the value of linezolid MIC is ≥8 mg/L or tedizolid MIC is ≥2 mg/L according to CLSI [17] and linezolid MIC is >4 mg/L or tedizolid MIC is >0.5 mg/L according to EUCAST [16] are classified as resistant. Resistance to oxazolidinones may result from mutations in the rrn5 gene, mutations in rplC, rplD, rplV genes encoding ribosomal proteins L3 (G152D substitution), L4 (K68Q substitution), L22, mutations and expression of cfr genes. These mechanisms also determine resistance to lincosamides, phenicols, streptograminA and pleuromutilin [75]. A mutation in the rpoB gene (A1345G; substitution in the RpoB protein D449N) was also described, which determines the resistance of S. aureus strain to linezolid (MIC = 8 mg/L) and tedizolid (MIC = 4 mg/L), chloramphenicol (MIC-128 mg/L), medium sensitivity to quinupristin/dalphopristin (MIC-2 mg/L) [94]. Mutation in the rrn5 gene encoding 23S rRNA in the 50S subunit of the ribosome results in modification of the target site for linezolid within the V domain of the 23S rRNA and prevents linezolid action. Among strains isolated from clinical cases, the G2576U mutation (G2576T in rDNA) appears to be the most significant. This mutation has been found in single S. aureus strains [95,96]. In one linezolid-resistant S. aureus strain another mutation of the rrl5 gene, namely T2500A, was found, in the absence of G2576U, G2447T mutations were also described [75,96]. It was found that for four resistant clinical isolates of S. aureus, characterized by linezolid MIC values of 16 mg/L (three strains) and 8 mg/L (one strain), the G2576T mutation was always present in two alleles out of five, with copy 5 (rrn5) always present [96].
A different mechanism of resistance to oxazolidinones involves the synthesis of an adenylyl-N-methyltransferase Cfr that causes dimethylation of adenine (A2503) within the V domain of 23S rRNA of bacterial ribosome (Figure 1). The cfr gene was found in plasmid p004-737X (istAS-istBS-cfr-tnp) of 55 kb [97]. The occurrence of Cfr has been described in S. aureus in the Tn556 transposon embedded in plasmid pSCFS6 (GenBank AM408573) [98,99]. Expression of the cfr gene causes resistance to oxazolidinones (linezolid), lincosamides, phenicoles (chloramphenicol), streptogramin A (dalfopristin) and retapamulins (pleuromutilin) [97].
Another mechanism is conditioned in S. aureus by ARE ABC-F (antibiotic resistance (ARE) proteins belong to the F lineage of the ABC superfamily) proteins such as OptrA conditioning resistance to linezolid and phenicols and PoxtA protein conditioning resistance to linezolid, phenicols and tetracyclines through a ribosomal protection mechanism [100,101].

5. Resistance to Macrolides, Lincosamides, Ketolides and Streptogramins B

Most of the macrolides, lincosamides and streptogramins B (MLS-B) show the same mechanism of action. The target site for them is a four-nucleotide rRNA fragment (in the peptidyltransferase region) within the V domain of the 23S rRNA, in the 50S subunit of the ribosome. A different mechanism is demonstrated by the macrolide antibiotic approved by the FDA for the treatment of Clostridioides difficile infections, fidaxomicin, which inhibits DNA-dependent RNA polymerase [102]. Resistant S. aureus have MIC azithromycin, clarithromycin, erythromycin, dirythromycin ≥ 8 mg/L and MIC clindamycin ≥ 4 mg/L according to CLSI [17] and MIC azithromycin, clarithromycin, erythromycin > 2 mg/L and MIC clindamycin > 0.25 mg/L according to EUCAST [16].
There are various mechanisms of S. aureus resistance to MLS-B antibiotics. The most common mechanism involves modification of the target site for the antibiotic. The modification is carried out by the enzymes adenylyl-N-methyltransferase Erm (erythromycin ribosome methylation) (Figure 1), dimethylating adenine 2058, which leads to resistance to all MLS-B. The gene encoding Erm methylase synthetase may be expressed in a constitutive manner, in which case strains show resistance to all MLS-B, or in an inducible manner, in which case resistance occurs only to antibiotics that are inducers of methylase synthesis, i.e., macrolides with a 14-member ring (M14) except ketolides (e.g., erythromycin, clarithromycin, oleandomycin) and 15-member ring (M15, e.g., azithromycin) [103]. Resistance to the other MLS-B requires the presence of an inducer, which may be erythromycin or another macrolide M14-15 [104]. CLSI’s introduction of an inducible MLS-B resistance test for staphylococci and streptococci into routine testing was intended to preclude the use of clindamycin in patients infected with bacteria that, although showing sensitivity to this antibiotic, can very easily become resistant to it during treatment. Inducible resistance to MLS-B in S. aureus is most often determined by the ermA or ermC genes [103]. The frequency of formation of constitutive variants from inducible ermA genes has been determined to be approximately 10−6–10−8, and for inducible ermC genes, the frequency is usually much higher. Causes of constitutive variants are deletions, duplications, insertions, and, relatively rarely, point mutations located in a region about 200 bp upstream of the 5′ end of the erm gene. Differences in frequency of constitutive variants formation are probably connected with different localization and a different number of copies per cell of ermA and ermC genes. The ermA gene, found in S. aureus in the chromosome as part of the Tn554 transposon (containing the ermA gene and the spc gene for resistance to spectinomycin), has one site of high preference and another site of 1000× less preference for integration into the chromosome. Tn554 is mostly found in one copy per chromosome. In MRSA strains, Tn554 is additionally present in SCCmec type II, III or VIII cassettes. The ermA gene has also been described in the Tn6072 transposon (GenBank GU235985) [105]. The ermC gene encoding a 23S rRNA (adenino 2085-N6)-dimethyltransferase (EC 2.1.1. 184) is mostly located within small plasmids such as pE194 (GenBank V01278) [106], pT48 (GenBank M19652) [107], pE5 (GenBank M17990) [108], pJR5 (GenBank L04687) [109], pA22 (GenBank X54338) [110], pJ3356::POX7 (GenBank U36911) [111], pWBG738 with a size of 2.5–5.0 kb, found in high copy number and within large conjugation plasmids, e.g., pUSA03 (37 kb), where it occurs together with the ileS2 gene that conditions mupirocin resistance [112,113].
Regulation of ermA and ermC gene expression occurs at the translational stage. The ermA gene is preceded in the polycistronic strand by two genes encoding leader peptides: pepL and pep1, whereas in the case of ermC by one, pep. The bundled structures formed by rRNA pep prevent ribosome access to the RBS (ribosome binding site) for the erm gene. Therefore, in the absence of an inducer, Erm methylase synthesis does not occur. On the other hand, if an inducer molecule (M14-15.) binds to the ribosome beforehand, translation of the leader peptide is interrupted and dissociation of the ribosome does not occur. This results in a permanent bifurcation of the mRNA spliced structure, allowing ribosome access to the RBS for the erm gene and its translation (Figure 4) [113]. Point mutations (G98A, A137C, C140T and G205A) in the regulatory region of the ermA gene have been described. The ermA gene in which the G98A, A137C and C140T mutations were present (phenotypes 1 and 2) did not show expression of azithromycin and clindamycin resistance [114]. Other mechanisms of resistance to MLS-B have also been described in S. aureus strains.
Synthesis of 23S rRNA methylases other than Erm(A) and Erm(C) that modify the target site for the antibiotic: Erm(GM), (another name for Erm(Y)), the ermGM gene occurs in plasmid pMS97, (GenBank AB014481) [115]; Erm(B), the ermB gene occurs in Tn551 often described in hMRSA and VRSA chromosome and in pI258 (GenBank AB300568) [82,116,117]; Erm(F) [118]; Erm(T) [119]; Cfr conditions resistance to lincosamides and some antibiotics of other groups [82,97].
Synthesis of efflux pumps proteins such as ABC proteins Msr(A), Msr(A)/Msr(B) (M14SB resistance) [120,121,122] and MsrSA (GenBank AB013298, M14-15SB resistance) [123]; Vga(A) proteins (clindamycin and lincomycin resistance) [124].
Synthesis of MLS-B-inactivating enzymes such as macrolide phosphotransferases Mph(BM) (GenBank AB013298) and Mph(C) described in plasmids pMS97, pSR1 (GenBank AF167161) and in animal biotypes of S. aureus [113,125,126]; Lnu(A) nucleotidyltransferase (other names LinA, LinA1, or LinA’; lincomycin resistance) [127,128]; Ere(A), Ere(B) esterases (M14,16 resistance) [129]; and VgbA, VgbB, inactivating streptogramin B lyases [130,131,132].
Resistance to MLS-B can also result from mutations in chromosomal genes encoding ribosomal proteins, such as a mutation in the rplV gene encoding the L22 protein in the 50S subunit of the ribosome, which determines resistance to erythromycin, telithromycin, quinupristin, and dalfopristin in S. aureus [133] and a mutation in the rplD gene encoding the L4 protein in the 50S subunit of the ribosome that conditions resistance to erythromycin and spiramycin in S. aureus [134].

6. Resistance to Aminoglycosides and Spectinomycin

Aminoglycosides are bactericidal antibiotics that inhibit protein synthesis by interfering with the 30S subunit of the ribosome. Breakpoints of resistant S. aureus to gentamicin and tobramycin are MIC > 2 mg/L and to amikacin are MIC > 16 mg/L according to EUSAST [16] and gentamicin MIC ≥ 16 mg/L according to CLSI [17]. In routine diagnostics in S. aureus, only gentamicin resistance is determined. Gentamicin-resistant S. aureus strains (those having the aacA-aphD gene) are usually resistant to all aminoglycoside antibiotics currently used in human therapy, distreptamine derivatives.
Resistance to aminoglycosids in S. aureus may result from various mechanisms such as: (1) Synthesis of transferases (acetyltransferases, phosphotransferases, nucleotidyltransferases) that modify the aminoglycoside molecule [135,136,137]. The only aminoglycoside not modified by most enzymes (except AAC(2′)-Ia,b,c) is plazomicin, but it is currently not recommended for the treatment of S. aureus infections [138]. (2) Lack of enzymes responsible for active transport of aminoglycosides into the bacterial cell (anaerobic metabolism of S. aureus, e.g., within biofilm; S. aureus SCV, small colony variant; S. aureus subsp. anaerobius) [139].
The most common mechanism of resistance to aminoglycosides in S. aureus is the synthesis of enzymes of the transferase group (Figure 1) [135,140,141,142,143,144]. The most significant are: the two-domain acetyltransferase/phosphotransferase AAC(6′)-Ie/APH(2”)-Ia, encoded by the aacA-aphD gene and causing resistance to gentamicin, tobramycin, kanamycin, amikacin and netilmicin, ANT(4′)-Ia nucleotidyltransferase encoded by aadD gene and causing resistance to tobramycin, kanamycin, neomycin and APH(3′)-IIIa phosphotransferase encoded by aph(3)-IIIa gene causing resistance to kanamycin, neomycin, and lividomycin [141]. An APH(3′)-III phosphotransferase conditioning resistance to kanamycin and neomycin, encoded by the aphA-3 gene (another name for the aph(3)-IIIa gene), has also been described in vancomycin-resistant S. aureus (VRSA). This gene is found within the transposons Tn3851, Tn4031 and Tn5404, located on plasmids transmitted to S. aureus from Enterococcus spp. [82].
The aacA-aphD genes (another gene name aac(6)-Ie-aph(2”)-Ia gene) encoding AAC(6′)-Ie acetyltransferase/APH(2”)-Ia phosphotransferase are found in Tn4001, Tn4001-like transposons located in large plasmids, e.g., pSK1 (GenBank GU565967), VRSAp present in strain Mu50 (GenBank AP003367) and in chromosomes, e.g., in SCCmec IV (2B&5) and, according to former nomenclature, in SCCmec IVc cassettes [145]. The aacA-aphD genes occurring together with the ermA methylase genes (MLS-B resistance) and the spc gene for spectinomicin resistance were described in the Tn6072 transposon (GenBank GU235985) [105]. AAC(6′)-Ie/APH(2”)-Ia is the only enzyme in S. aureus known so far to determine gentamicin resistance. The MIC of gentamicin for strains that produce this enzyme ranges from 8 mg/L to > 1024 mg/L. The MIC50 of gentamicin determined on a large population of S. aureus strains was 128 mg/L, and the MIC90 was 512 mg/L [141]. For strains sensitive to aminoglycosides and strains synthesizing ANT(4′)-Ia or APH(3”)-IIIa enzymes, gentamicin MIC values are in the range of 0.25–1.0 mg/L. Synthesis of AAC(6′)-Ie/APH(2”)-Ia also usually determines resistance to tobramycin. The MIC of tobramycin for strains synthesizing this enzyme, ranges from 8 mg/L to 256 mg/L (MIC50 is 32 mg/L and MIC90 is 64 mg/L) [141]. Moreover, strains synthesizing this enzyme are always resistant to kanamycin (MIC64 mg/L). The only enzyme in S. aureus that degrades netilmicin is AAC(6′)-Ie/APH(2”)-Ia. Netilmicin is a very weak inducer of the aacA-aphD gene, which is the reason that S. aureus strains having an inducible mechanism of regulation of this gene are often designated as sensitive in routine testing. Ida et al. [146] described natural S. aureus strains in which Tn4001-like elements containing the aacA-aphD gene retained the promoter of the beta-lactamase operon (reduced blaZ gene), which can result in strong induction of aminoglycoside resistance by beta-lactam antibiotics and antagonism of beta-lactams and aminoglycosides. Using aztreonam at 25 mg/L as an inducer, an increase in the MIC values of netilmicin from 4 to 32 mg/L and gentamicin from 128 to 1024 mg/L was obtained [146]. Some point mutations of the aacA-aphD gene can extend the spectrum of AAC(6′)-Ie/APH(2′′)-Ia by, for example, arbekacin [147].
The aadD gene (other gene names: ant(4)-Ia, aadD2, ant(4,4′′)-I) encoding ANT(4′)-Ia nucleotidyltransferase, is found in both conjugative plasmids, e.g., pGO1 of 54 kb (GenBankNC_012547) or pSK41 of 46.5 kb (GenBank AF051917), as well as in smaller non-conjugative plasmids such as pKKS825 of 14.3 kb (GenBank NC_013034) or pUB110 of 5.1 kb (GenBank AB037420). A copy of pUB110 is present in SCCmec type IA and type II chromosomal methicillin cassettes [29,53].
The aph(3)-IIIa gene encoding the APH(3′)-IIIa phosphotransferase is most commonly found in plasmids and within the plasmid-embedded transposons Tn3851, Tn4031 and Tn5404 [82]. APH(3′) encoded by the aphA-3 gene (GenBank AB300568) has also been described [117,148,149]. APH(3′)-IIIa conditions resistance to kanamycin, neomycin, paromomycin, lividomycin, livostamycin, isepamycin, butyrosin and amikacin. The high MIC of lividomycin (> 1024 mg/L) allows phenotypically distinguishing this gene from the others [146].
The aadE gene (other names ant(6), ant(6)-Ia) in plasmid pS194 encodes the ANT(6)-Ia nucleotidyltransferase that conditions streptomycin resistance [82,117].
The aadA5 cassette gene encoding ANT(3”)-Ia nucleotidyltransferase that conditions resistance to streptomycin and spectinomycin was described in a class I integron structure (GenBank AB481128) [8,150].
The spc gene (another name for the aad(9) gene, ant(9)-Ia) encoding the ANT(9) nucleotidyltransferase (another name for ANT(9)-Ia) that conditions resistance to spectinomycin was described in the Tn554 and Tn6072 transposons in S. aureus (GenBank X02588, GU235985).

7. Resistance to Fluoroquinolones

Fluoroquinolones are classified as bactericidal drugs. They inhibit the activity of topoisomerase II (gyrase) and topoisomerase IV enzymes, responsible for DNA superspiralization and respiralization. According to EUCAST [16], the breakpoints for ciprofloxacin and levofloxacin are MIC > 1 mg/L, for moxifloxacin MIC > 0.25 mg/L and delafloxacin MIC > 0.25 mg/L (for skin and skin structure infections) or MIC > 0.016 mg/L (environmental pneumonia). According to CLSI [17], the limits for ciprofloxacin, levofloxacin, grepafloxacin, ofloxacin are MIC ≥ 4 mg/L and for moxifloxacin, gatifloxacin, sparfloxacin MIC ≥ 2 mg/L.
Fluoroquinolone resistance in S. aureus is caused by mutational changes in the gyrA and gyrB (topoisomerase II) and parC (grlA) and are (topoisomerase IV) genes. The mutations result in the synthesis of proteins with reduced susceptibility or insensitivity to fluoroquinolones [145]. Overproduction of the chromosome-encoded proteins responsible for efflux of fluoroquinolones from the bacterial cell (NorA, NorB, NorC and SdrM, all MFS superfamily) has also been described as a cause of the resistance [150,151]. In S. aureus, mutations in gyrA and grlA genes have been most frequently described. In the gyrA gene, the most common mutations are those causing the following substitutions in the GyrA topoisomerase II protein: S84L, A, V, or K; S85P; E86K, or G; E88V, G or K; Gl06D. In the gene encoding ParC (grlA), the most common mutations cause the following substitutions in the ParC topoisomerase IV protein: K23N; V4lG; R43C; I45M; A48T; S52R; D69Y; G78C; S80F, or Y; S8lP; E84K, L, V, A, G, or Y; H103Y; Al16E, or P; Pl57L; A176T, or G; N327K and P451S substitution in the ParE protein [125,152,153].

8. Resistance to Tetracyclines

Tetracyclines inhibit protein synthesis by interfering with the 30S subunit of the ribosome. Breakpoints of resistance to tetracycline, doxycycline and minocycline are MIC ≥ 16 mg/L according to CLSI [17] and according to EUCAST [16] for tetracycline and doxycycline MIC > 2 mg/L and minocycline and tigecycline MIC > 0.5 mg/L and MIC > 0.25 mg/L for eravacycline.
The mechanism of resistance to tetracyclines in S. aureus usually involves active removal of the antibiotic from the bacterial cell and ribosomal protection.
Active removal of tetracyclines from the S. aureus cell is conditioned by the membrane proteins Tet(K), Tet(L), Tet(38), Tet(42), Tet(43), Tet(45), Tet(63) that derive their energy from the proton pump and are classified as MFS. Most commonly, this mechanism is represented by the Tet(K) protein having 14 transmembrane segments (14 TMS) and often causes resistance to tetracyclines, except minocycline. The tet(K) gene has been described in plasmids pT181 (GenBank S67449) [154], pSTE2 (GenBank NC_006871), pNS1 (GenBank M16217) [155], pKH1 (GenBank U38656) [156], pKH6 (GenBank U38428) [156], pT127, pBC16. Plasmid pT181 is also found in SCCmec type III chromosomal cassettes [43]. Tet(L) protein having 14 TMS was described in plasmid pKKS825 (GenBank NC_014156) [116]. The gene encoding the Tet(38) protein was located in genomic DNA (GenBank AY825285) [157]. The gene encoding the 14 TSM-positive Tet(63) protein was detected in the 25664 bp plasmid pSA01-tet. The plasmid also had the genes aacA-aphD and aadD (aminoglycoside resistance) and ermC (MLS-B resistance) [100].
Active protection of the drug target site (ribosomal protection) involves dissociation of the tetracycline molecule from the 30S subunit of the ribosome by Tet(M) and Tet(S) proteins [82,116,158]. The Tet(M) protein determines resistance to tetracyclines including minocycline and is often the cause of resistance to tetracyclines in S. aureus. The tet(M) gene is present in the chromosome of many S. aureus strains, such as Mu3 and Mu50 (GenBank NC_009782, NC_002758, M21136) [120,159], and has also been described in the Tn6014 transposon (Tn5801-like) [160]. Plasmid tet(S) genes are characteristic of VRSA strains [82].
Resistance conditioned by Tet(U) proteins encoded by plasmids in S. aureus, most commonly found in VRSA strains, has also been described, but the mechanism of this resistance has not been understood to date [82]. Tetracycline resistance in Staphylococcus spp. conditioned by Tet(O), Tet(W) and Tet(44) proteins conditioning ribosomal protection has also been described [100].

9. Resistance to Mupirocin

Mupirocin inhibits protein synthesis by inactivating isoleucyl-tRNA synthetase. Topical drug used to decolonize MRSA and MSSA among healthcare personnel. No CLSI or EUCAST resistance criteria.
The cause of mupirocin resistance in S. aureus is the production of an isoleucyl-t-RNA synthetase encoded by the mupA gene (another name for the ileS2 gene) that is insensitive to mupirocin. The mupA gene was described in the 37.1 kb conjugative plasmid pUSA03 (ileS2 gene, GenBank CP000258) [112], in plasmids pJ2947 (GenBank acc. X59477, X59478) [161], MupR plasmid (GenBank DQ102365), MupR type I, II and IV plasmids (GenBank EU442885, EU442888, EU442886) [162], pJ3358, pGO400. The presence of the mupA gene conditions the MIC of mupirocin from 500 to >1000 mg/L [159,163,164,165,166]. A plasmid mupB gene of 3102 bp has also been described in S. aureus mupB gene shows 65.5% identity with mupA and 45.5% identity with ileS gene and conditions mupirocin resistance (MIC1024 mg/L). The plasmid containing the mupB gene could not be transferred to other S. aureus strains. The three strains in which the mupB gene was detected belonged to the EMRSA-2 clone (CC5/ST5) [167]. Mutations in the chromosomal ileS gene encoding isoleucyl-t-RNA synthetase and V58F or V631F substitutions in the IleS protein condition S. aureus to have reduced sensitivity to mupirocin (MIC 8–16 mg/L) [125,168].

10. Resistance to Fusidic Acid

Fusidic acid inhibits protein synthesis by interaction with elongation factor G (EF-G). Breakpoint of resistance to fusidic acid is MIC > 1 mg/L according to EUCAST [16]. CLSI does not provide a criterion.
Several mechanisms of resistance to fusidic acid in S. aureus have been described. The first mechanism is associated with mutations in the fusA or fusA-SCV genes encoding the elongation factor (EF-G). Therefore, conditioned resistance to fusidic acid is referred to as the FusA phenotype [169]. Mutations may also affect the fusE gene (rplF) encoding ribosomal protein L6 interacting with EF-G in the 30S subunit of the ribosome. The fusidic acid resistance thus conditioned is referred to as the FusE phenotype [169]. Another mechanism is related to active protection of the elongation factor. Active protection of EF-G is caused in S. aureus by FusB and FusC proteins encoded by fusB and fusC genes. The fusC gene has also been described in staphylococcal cassette chromosome (SCCfus) [170]. The FusD protein encoded by the fusD gene has also been described in S. saprophiticus. [169]. The fusB gene that conditions the MIC of fusidic acid from 8 to 16 mg/L was described in penicillinase plasmids in strains (FAR1 and FAR2 and FAR4 to FAR19) as early as 1974 [171], but the mechanism of resistance was understood much later. In 2002, the fusB gene was described in plasmid pUB101 (GenBank AY047358) [172,173] and in resistance island RASIfusB (GenBank AM292600) [174].

11. Resistance to Daptomycin

Daptomycin, a cyclic lipopeptide antibiotic that acts on the cytoplasmic membrane of S. aureus. Daptomycin aggregation with the cytoplasmic membrane is a Ca2+ ion-dependent process leading to pore formation, release of intracellular ions leading to S. aureus cell death. S. aureus strains with MIC > 1 mg/L daptomycin are defined as resistant by EUCAST [16]. Resistance or reduced sensitivity to daptomycin is probably related to mutations in the mprF gene encoding lysyl-phosphatidylglycerol synthetase (N352K substitution in MprF), dltABCD operon responsible for D-alanine attachment to teichoic acids in the cell wall (substitutions of N276S in DltB and P309L inDltD), vraSR regulatory genes and clpP (ATP-dependent Clp protease; G74S substitution), rpoC (RNA polymerase subunit), vraG (ABC transporter, permease protein), spsB (signal peptidase; R159S substitution), fmtA (autolysis and methicillin resistance-related protein), asp23 (alkaline shock protein 23; E47K substitution in Asp23), yycG (synonyms: walK, vicK; sensor histidine kinase; substitutions: D408G, R463Q), pgsA (phosphatidylglycerolphosphate synthetase) [75,175,176,177,178].

12. Other Antibiotics

12.1. Resistance to Streptogramins A and Quinupristin-Dalfopristin

Streptogramins A (e.g., dalfopristin, pristinamycin) act on the 23S rRNA of the 50S subunit of the ribosome, but at a different site than MLS-B. Breakpoints of resistance are reported only for quinupristin-dalfopristin (streptogramins A/streptogramins B) and are MIC > 2 mg/L according to EUCAST [16] and MIC ≥ 4 mg/L according to CLSI [17].
Resistance to streptogramins A in S. aureus may result from the production of enzymes that inactivate streptogramins A such as Vat acetyltransferases encoded by the plasmid genes vatA [179], vatB located in the Tn5406 transposon [180,181], vatC [130], vatD, vatE [130] or Vgb lyases encoded by the vgb(A) and vgb(B) genes [131]. Resistance may also be conditioned by membrane proteins Vga (ATP-binding proteins) which are responsible for the efflux of streptogramin A. Vga are encoded by the plasmid and transposon genes vga(A), vga(Av) in Tn5406, vga(B), vga(C) and vga(E) in Tn6133 [180,182,183,184]. A membrane protein, Vga(A)LC, has also been described conditioning resistance to clindamycin (MIC 8–32 mg/L), lincomycin, and streptogramin A with concomitant sensitivity to erythromycin (MIC 0.094–0.19 mg/L). The vga(A)LC gene has been described in plasmids in S. aureus [124]. The production of Cfr methyltransferase that modifies the target site for streptogramin A, among others, may also be the cause of streptogramin resistance [97].
The synergistic action of streptogramins A (dalfopristin) and streptogramin B (quinupristin) causes a killing effect on S. aureus (including MRSA, VRSA, VISA). After quinupristin-dalfopristin treatment, a post-antibiotic effect (PAE) occurs, consisting of further inhibition of bacterial growth at drug concentrations less than the MIC. PAE values were for: S. aureus 2–8 h [185,186]. Resistance to quinupristin-dalfopristin in S. aureus is most often due to the presence of two mechanisms: constitutive resistance to MLS-B and resistance to streptogramin A. Moreover, mutation of the chromosomal gene encoding ribosomal protein L22 causes resistance of the S. aureus strain to quinupristin-dalfopristin [133].

12.2. Resistance to Rifampicin

Rifampicin inhibits transcription by interfering with the beta subunit of RNA polymerase. Breakpoint of resistance to rifampicin in S. aureus is MIC > 0.06 mg/L according to EUCAST [16]. CLSI reports a breakpoint of rifampin resistance in S. aureus (MIC ≥ 4 mg/L) [17].
Resistance to rifampicin in S. aureus is determined by mutations in the rpoB gene encoding the B subunit of RNA polymerase [187]. The most common are mutations that cause amino acid sequence changes in the RpoB protein, such as V453F, S464P, L466S, D471N A473D, A477D or T, H481N or Y, and I527L or M [125,188].

12.3. Resistance to Chloramphenicol

Chloramphenicol is a broad-spectrum antibacterial antibiotic that penetrates well into the cerebrospinal fluid. Due to side effects, its use has been greatly restricted. Breakpoint for resistant S. aureus strains is MIC ≥ 32 mg/L according to CLSI [17] or MIC > 8 mg/L according to EUCAST [16].
The cause of chloramphenicol resistance is the synthesis of chloramphenicol acetyltransferases CATA7, CATA8, CATA9 or active removal of chloramphenicol from the bacterial cell by membrane proteins belonging to the MFS superfamily CmlA1, having 12 transmembrane segments (TMS) and FexA protein with 14 transmembrane elements [189], and synthesis of adenylyl-N-methyltransferase Cfr conditioning resistance to chloramphenicol, linezolid, lincosamides, streptogramins A and pleuromutilin [97].
Resistance to chloramphenicol may also result from mutations in the rrn5 gene, mutations in rplC, rplD, rplV genes encoding ribosomal proteins L3 (G152D substitution), L4 (K68Q substitution), L22. These mechanisms also determine resistance to oxazolidinones, lincosamides, streptogramins A and pleuromutilin [75]. A mutation in the rpoB gene (A1345G; substitution in RpoB protein D449N) was also described, conditioning the resistance of S. aureus strain to chloramphenicol (MIC-128 mg/L) and intermediate to oxazolidinones [94].
CATA7 acetyltransferase is encoded by cat genes present in plasmids pC221 (GenBank X02529) [190], pKH7 (GenBank U38429) [191], pUB112 (GenBank X02872,) [192], pSCS6 GenBank X60827) [193]. CATA8 acetyltransferase is encoded by cat genes present in plasmids pC223, pSCS7, pSBK203 (GenBank NC_005243, AY355285) [194,195]. CATA9 acetyltransferase encoded by cat genes present in plasmids pC194 (GenBank V01277), pMC524-MBM (GenBank AJ312056) [196]. The membrane protein CmlA1 (419 aa, 12 TMS) is encoded by cmlA1 or cmlA genes, which have been described in S. aureus in class I integron (GenBank AB481130) [9]. The membrane protein FexA has been described in S. aureus with the ST8-MRSA-IVa/USA300 genotype (GenBank FN995110). In addition to resistance to chloramphenicol, it also conditions resistance to florphenicol [99].

12.4. Resistance to Fosfomycin

Fosfomycin is an inhibitor of MurA enzyme (UDP-N-acetylglucosamine-enolpyruvyltransferase) which results in inhibition of peptidoglycan synthesis. Breakpoints of resistance are MIC > 32 mg/L according to EUCAST [16].
The cause of phosphomycin resistance is the synthesis of the metalloenzyme FosB (EC 2.5.1.-) that catalyzes the Mg2+-dependent attachment of L-cysteine to the phosphomycin ring [197]. FosB has been described in the chromosomes of VISA and hVISA S. aureus strains Mu50 and Mu3 (GenBank NC_002758, NC_009782), among others [198].

12.5. Resistance to Trimethoprim

Trimethoprim is a drug used alone and in combination with sulfamethoxazole. Breakpoint of resistance is MIC > 4 mg/L according to EUCAST [16] and MIC ≥ 16 mg/L according to CLSI [17]. The cause of trimethoprim resistance is the synthesis of dihydrofolate reductase (DHFRS1) (EC encoded in S. aureus by dfrA, dfrK, the cassette genes dfrA12 and dfr15 [8,9,119,120,199] and dfrG found in SCCmec [63]. The dfrA gene has been described in the Tn4003 transposon [197] located in plasmid pSK1 (GenBank GU565967) and in plasmids pJE1 (GenBank AF051916) and pABU1 (GenBank Y075376), among others [200]. The dfrK gene has been described in plasmid pKKS825 (GenBank NC_013034), pKKS627 (GenBank NC_014156) and in transposon Tn559 (GenBank FN677369) [201,202]. The cassette genes dfrA12 and dfr17 have been described in the class I integron structure (GenBank AB191048, AB291061) [8,9]. Substitutions of F99Y, L21Y and L41F in the DHFR protein encoded by the chromosomal dfrB gene may also be the cause of trimethoprim resistance [125].

13. Molecular Epidemiology of MRSA

The spread of MRSA is clonal. In different years, in specific geographical areas or under specific conditions (hospital, community), specific clones predominate. In general, MRSA are subdivided according to the origin of the first isolates into HA-MRSA, CA-MRSA, and LA-MRSA. Clonal affiliation, and thus presumed descent from a common ancestor, is assessed based on demonstration of similarity by several different molecular typing methods. In the case of S. aureus these are mainly MLST, Spa (a polymorphic VNTR in the 3′ coding region of the S. aureus-specific staphylococcal protein A) typing, and particularly important is the SCCmec cassette typing. A high correlation of sequence types with the presence of some pathogenicity genes and the type of the Agr regulatory system was observed.
The pathogenicity factors of S. aureus are very diverse and can be classified into several basic groups.
The first group includes pathogenicity factors that protect bacteria from the host immune system. It contains: proteins that inhibit the complement system: Sbi (Staphylococcus aureus binder of IgG), Efb (extracellular fibrinogen binding protein), Ecb (extracellular complement binding protein) and Scn (SCIN, staphylococcal complement inhibitor situated on a hlb-integrating phage SA3), chemotaxis-inhibiting protein (CHIPS) situated on a hlb-integrating phage SA3 [203,204], immunoglobulin binding proteins: SpA (immunoglobulin G binding protein A), Sbi (immunoglobulin binding protein), factors responsible for biofilm formation (PIA-dependent biofilm (polysaccharide intercellular antigen), PIA-independent biofilm and biofilm formed from extracellular DNA (eDNA) [205], and superantigens and superantigen-like proteins (SSL), about 40 proteins, including most enterotoxins, like-enterotoxin, toxic shock toxin TSST-1, SSL1-SSL14 proteins [206]. S. aureus cells are either neutralized by the defense forces of the human organism or they break these barriers and enter the phase of intensive multiplication, the so-called logarithmic growth phase (the generation time of S. aureus is about 20 min). After reaching an appropriate density, the bacteria stop dividing and enter the stationary phase where they start to synthesize toxins (invasive infections) or form a biofilm (chronic infections). Beta-lactam antibiotics and glycopeptides, the two most important groups of drugs in the treatment of S. aureus infections, have no effect on bacteria in the stationary phase. Biofilm formation by S. aureus hinders the penetration of drugs inside the biofilm (especially multi-molecule drugs such as glycopeptides) which results in drugs inside the biofilm not reaching the MIC let alone the MBC. Moreover, some S. aureus cells inside the biofilm switch to anaerobic metabolism which is associated with resistance to aminoglycosides.
The next group consists of factors enabling S. aureus colonization. We include here adhesive proteins such as proteins binding covalently with nasal epithelium: ClfB (clumping factor B), SasG (S. aureus surface protein G), Pls (plasmin sensitive protein), IsdA (iron-regulated surface determinant protein A), SdrC, SdrD (serine-aspartate repeat-containing proteins C and D); fibrinogen-binding proteins: FnbpA, FnbpB (fibronectin binding proteins A and B), ClfA, ClfB (clumping factor A and B), SdrE (serine-aspartate repeat-containing protein E), IsdA forming a covalent bond and Atl (major autolysin and adhesine) [207], Aaa (two-domain autolysin/adhesin protein) [208], Eap (extracellular adherence protein), Emp (non-covalent binding); Fibronectin-binding proteins: FnbpA, FnbpB, IsdA, (covalent binding) Atl, Aaa, Eap, Emp, Ebh (extracellular matrix-binding protein)—non-covalent binding; elastin-binding proteins: FnbpA, FnbpB (covalent binding), EbpS (elastin binding protein S)—non-covalent binding; collagen binding proteins: Cna (collagen binding adhesin)—covalent binding, Eap, Emp (non-covalent binding); bone sialoprotein covalent binding protein Bbp; glycolipid covalent binding protein Pls; vitronectin non-covalent binding proteins: Atl, Aaa, Eap, Emp; and the endoprosthesis polystyrene-binding protein Bap (biofilm-associated protein), SasC (covalent binding), Atl (non-covalent binding) [209,210]. Activation of SpA protein interaction with vWF glycoprotein may promote bacterial adhesion to damaged blood vessels [211]. This group of factors may also include products of genes encoded by ACME (arginine catabolic mobile element) that enable skin colonization.
The next group of pathogenicity factors are toxins and enzymes. Here we include hemolysins (Hla, Hlb, Hld); leukotoxins (synergohymenotropic toxins, interaction of 2 proteins one from group F and one from group S): LukF-PV/LukS-PV, HlgB/HlgA, LukF/LukS, LukD/LukE, LukF-PV/LukM, LukG/LukH; PSM (phenol soluble modulins) toxins: PSMalpha, PSMbeta; enterotoxins (SE) and enterotoxin-like (SEl): SEA-SEE, SEG-SEJ, SER-SET, SElK-SElQ, SElU-SElX; epidermolytic toxins ETA, ETB, ETD; and toxic shock toxin TSST-1 [13]. S. aureus also produces many enzymes and other proteins categorized as pathogenicity factors such as SplA-SplF and V8 (serine proteases and serine like proteases), ScpA (cysteine protease), Aur (zinc metalloproteinase aureolysin), Geh1 and Geh2 (Lip1 and Lip2; lipase1 and lipase2), HY-ase (hyaliauronate lyase), ceramidase [212], SrtA (sortase), and other protein factors such as Coa (coagulase, coagulation mediator), vWbp (von Willebrand binding protein) [213], EdinA-EdinC (epidermal cell differentiation inhibitor) and EDIN-like exotoxin [214]. Another group includes systems that take up iron from heme (ISD and HtsBC), from hemoglobin (ISD) and transferrin (siderophores, staphyloferrins A and B) [215,216]. Global and local regulatory systems are another group that determines the expression of many pathogenicity factors. Activity of the global Agr (accessory gene regulator, quorum sensing system)/SarA (staphylococcal accessory regulator A) system and high activity of the SaeS/R (Staphylococcus aureus exoprotein expression response regulator) system results in the synthesis of hemolysins, leukotoxins, PSM toxins (PSM1-4, PSM1-4), proteases, lipases, and proteins that protect S. aureus from the immune system (Sbi, Efb, Scn, Chp) and is more frequently observed in acute infections (invasive phenotype) caused by CA-MRSA.
In CA-MRSA strains SCCmec type IV, leukotoxin PVL and other leukotoxins are the most frequent and pathogenicity islands such as Sa1, Sa2, e.g., SR434 (ST88), Sa3, e.g., FR3757 (ST8), Sa4, e.g., MW2 (ST1) are more frequently detected, Sa, e.g., SR434 (ST88), Sa (contains leukotoxin lukDE genes), e.g., SR434 (ST88), Sa, e.g., SR434 (ST88), SAPISaitama (contains tst, sec, sel genes) (ST834) embedded in the DNA chromosome of bacteriophage SA1, SA2 (contains leukotoxin PVL genes) MW2 (ST1); FR3757 (ST8), SA3, the ACME eg FR3757 (ST8) element and many other pathogenicity genes [215,216].
Lack of Agr system activity leads to adhesion protein synthesis and biofilm formation (adhesion phenotype, chronic infections) and is characteristic of many HA-MRSA strains [8].
More important CA-MRSA clones according to [2,23,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232] are shown in Table 4, most important HA-MRSA clones according to [23,85,125,220,224,233,234,235,236] are shown in Table 5, and most important LA-MRSA clones according to [23,125,237,238,239,240,241,242] are shown in Table 6.

14. Conclusions

S. aureus can be classified as a major human pathogen. It is also one of the microorganisms most resistant to antibacterial drugs. A particular characteristic of these bacteria is the rapid spread of clones, characterized by higher virulence and resistance to many antibiotics. One of the most important, if not the most important event in the acquisition of resistance by S. aureus has been the emergence of methicillin-resistant strains and the associated presence of the mec cassette in the genome. Although there are different variants of this element, they all greatly affect the properties of the bacteria and especially facilitate the acquisition of resistance to other antibacterial drugs. The spread of strains containing the Van operon derived from enterococci would be a particularly big problem. MRSAs containing the VanA operon have been reported in the literature, but spread has fortunately been limited to date. The possibility of acquiring enzymatic resistance to oxazolidinones (Cfr) which is determined by mobile genetic elements (plasmid, transposon) is also of great concern. The possibility of rapid emergence and spread of resistance in S. aureus, and often associated altered virulence, creates the need for constant monitoring of emerging bacterial variants.

Author Contributions

Conceptualization, B.M.-B., W.M., C.K. and A.K.-U.; data curation, B.M.-B., W.M., C.K. and A.K.-U.; writing—original draft preparation, B.M.-B., W.M., A.K.-U. and C.K.; writing—review and editing W.M., C.K., B.M.-B. and A.K.-U.; visualization B.M.-B., W.M., A.K.-U. and C.K. supervision W.M., C.K., B.M.-B. and A.K.-U. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.


Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.


aaamino acids
AACaminoglycoside acetyltransferase
ABCATP-binding cassette transporter system
APHaminoglycoside phosphotransferase
Bpbase pair
CA-MRSAcommunity acquired MRSA
CCclonal complex
CFUcolony forming unit
CLSIClinical and Laboratory Standards Institute
CNScoagulase negative Staphylococci
DHAdrug:H+ antiporter
EF-Gelongation factor G
EUCASTEuropean Committee on Antimicrobial SusceptibilityTesting
GIgenomic island
GISAglycopeptide intermediate S. aureus
GRSAglycopeptide resistant S. aureus
GSSAglycopeptide sensitive S. aureus
HA-MRSAhospital acquired or health care acquired MRSA
h-GISAheterogeneous glycopeptide intermediate S. aureus
h-VISAheterogeneous vancomycin intermediate S. aureus
ISinsertion sequence
LA-MRSAlivestock associated MRSA
MBCminimal bactericidal concentration
MFSmajor facilitator superfamily;
MICminimal inhibitory concentration
MIC50MIC for 50% of strains tested
MIC90MIC for 90% of strains tested
MLS-Bmacrolide-lincosamides-streptogramin B
MLSTmultilocus sequence typing
MPHmacrolide phosphotransferase
MRSAmethicillin resistant S. aureus
MSSAmethicillin sensitive S. aureus
MurNAcN-acetylmuramic acid
orfopen reading frame
PAIpathogenicity island
PBPpenicillin binding protein
PFGEpulse field gel electrophoresis
PVLPanton–Valentine leukocidin
PMFproton-motive force
RBSribosome binding site
RNDresistance-nodulation-cell division superfamily
RPPsribosomal protection proteins
S. aureus SCVS. aureus small colony variants
SCCmecstaphylococcal chromosomal cassette mec
SpaS. aureus protein A
STsequence type
TMStransmembrane segments
TRSAteicoplanin resistant S. aureus
VISAvancomycin intermediate S. aureus
VRSAvancomycin resistant S. aureus
VSSAvancomycin sensitive S. aureus


  1. De Oliveira, D.M.P.; Forde, B.M.; Kidd, T.J.; Harris, P.N.A.; Schembri, M.A.; Beatson, S.A.; Paterson, D.L.; Walker, M.J. Antimicrobial resistance in ESKAPE pathogens. Clin. Microbiol. Rev. 2020, 33, e00181-19. [Google Scholar] [CrossRef] [PubMed]
  2. Hryniewicz, W. Epidemiology of MRSA. Infection 1999, 27, S13–S16. [Google Scholar] [CrossRef] [PubMed]
  3. Mlynarczyk, A.; Mlynarczyk, B.; Kmera-Muszynska, M.; Majewski, S.; Mlynarczyk, G. Mechanisms of the resistance and tolerance to beta-lactam and glycopeptide antibiotics in pathogenic gram-positive cocci. Mini Rev. Med. Chem. 2009, 9, 1527–1537. [Google Scholar] [CrossRef] [PubMed]
  4. Saha, B.; Singh, A.K.; Ghosh, A.; Bal, M. Identification and characterization of a vancomycin-resistant Staphylococcus aureus isolated from Kolkata (South Asia). J. Med. Microbiol. 2008, 57, 72–79. [Google Scholar] [CrossRef]
  5. Zhu, W.; Clark, N.C.; McDougal, L.K.; Hageman, J.; McDonald, L.C.; Patel, J.B. Vancomycin-resistant Staphylococcus aureus isolates associated with Inc18-like vanA plasmids in Michigan. Antimicrob. Agents Chemother. 2008, 52, 452–457. [Google Scholar] [CrossRef][Green Version]
  6. Limbago, B.M.; Kallen, A.J.; Zhu, W.; Eggers, P.; McDougal, L.K.; Albrecht, V.S. Report of the 13th vancomycin-resistant Staphylococcus aureus isolate from the United States. J. Clin. Microbiol. 2014, 52, 998–1002. [Google Scholar] [CrossRef][Green Version]
  7. McGuinness, W.A.; Malachowa, N.; DeLeo, F.R. Vancomycin resistance in Staphylococcus aureus. Yale J. Biol. Med. 2017, 90, 269–281. [Google Scholar]
  8. Shi, L.; Zheng, M.; Xiao, Z.; Asakura, M.; Su, J.; Li, L.; Yamasaki, S. Unnoticed spread of class 1 integrons in gram-positive clinical strains isolated in Guangzhou, China. Microbiol. Immunol. 2006, 50, 463–467. [Google Scholar] [CrossRef]
  9. Xu, Z.; Li, L.; Alam, M.J.; Zhang, L.; Yamasaki, S.; Shi, L. First confirmation of integron-bearing methicillin-resistant Staphylococcus aureus. Curr. Microbiol. 2008, 57, 264–268. [Google Scholar] [CrossRef]
  10. Butrico, C.E.; Cassat, J.E. Quorum sensing and toxin production in Staphylococcus aureus osteomyelitis: Pathogenesis and paradox. Toxins 2020, 12, 516. [Google Scholar] [CrossRef]
  11. Bush, K.; Jacoby, G.A. Updated functional classification of beta-lactamases. Antimicrob. Agents Chemother. 2010, 54, 969–976. [Google Scholar] [CrossRef] [PubMed][Green Version]
  12. García-Álvarez, L.; Holden, M.T.; Lindsay, H.; Webb, C.R.; Brown, D.F.; Curran, M.D.; Walpole, E.; Brooks, K.; Pickard, D.J.; Teale, C.; et al. Meticillin-resistant Staphylococcus aureus with a novel mecA homologue in human and bovine populations in the UK and Denmark: A descriptive study. Lancet Infect. Dis. 2011, 11, 595–603. [Google Scholar] [CrossRef][Green Version]
  13. Młynarczyk, A.; Młynarczyk, G.; Jeljaszewicz, J. The genome of Staphylococcus aureus: A review. Zentralbl. Bakteriol. 1998, 287, 277–314. [Google Scholar] [CrossRef]
  14. Livermore, D.M. β-Lactamases in laboratory and clinical resistance. Clin. Microbiol. Rev. 1995, 8, 557–584. [Google Scholar] [CrossRef]
  15. Balslev, U.; Bremmelgaard, A.; Svejgaard, E.; Havstreym, J.; Westh, H. An outbreak of borderline oxacillin-resistant Staphylococcus aureus (BORSA) in a dermatological unit. Microb. Drug Resist. 2005, 11, 78–81. [Google Scholar] [CrossRef]
  16. European Committee on Antimicrobial Susceptibility Testing (EUCAST) v. 12.0. 2022. Available online: (accessed on 30 May 2022).
  17. Standards M100-S32; Performance Standarts for Antimicrobial Susceptibility Testing. Twenty-First Information Supplement. Clinical and Laboratory Standarts Institute (CLSI): Wayne, PA, USA, 2022.
  18. Baba, T.; Bae, T.; Schneewind, O.; Takeuchi, F.; Hiramatsu, K. Genome sequence of Staphylococcus aureus strain Newman and comparative analysis of staphylococcal genomes: Polymorphism and evolution of two major pathogenicity islands. J. Bacteriol. 2008, 190, 300–310. [Google Scholar] [CrossRef][Green Version]
  19. Moreillon, P. New and emerging treatment of Staphylococcus aureus infections in the hospital setting. Clin. Microbiol. Infect. 2008, 14, 32–41. [Google Scholar] [CrossRef][Green Version]
  20. Ito, T.; Okuma, K.; Ma, X.X.; Yuzawa, H.; Hiramatsu, K. Insights on antibiotic resistance of Staphylococcus aureus from its whole genome: Genomic island SCC. Drug Resist. Updat. 2003, 6, 41–52. [Google Scholar] [CrossRef]
  21. Taxonomy Browser (Staphylococcus). Available online: (accessed on 3 February 2022).
  22. Cai, Y.; Zheng, L.; Lu, Y.; Zhao, X.; Sun, Y.; Tang, X.; Xiao, J.; Wang, C.; Tong, C.; Zhao, L.; et al. Inducible resistance to β-lactams in oxacillin-susceptible mecA1-positive Staphylococcus sciuri isolated from retail pork. Front. Microbiol. 2021, 12, 721426. [Google Scholar] [CrossRef]
  23. Lakhundi, S.; Zhang, K. Methicillin-resistant Staphylococcus aureus: Molecular characterization, evolution, and epidemiology. Clin. Microbiol. Rev. 2018, 31, e00020-18. [Google Scholar] [CrossRef][Green Version]
  24. Miragaia, M. Factors contributing to the evolution of mecA-mediated β-lactam resistance in Staphylococci: Update and new insights from whole genome sequencing (WGS). Front. Microbiol. 2018, 9, 2723. [Google Scholar] [CrossRef][Green Version]
  25. Becker, K.; van Alen, S.; Idelevich, E.A.; Schleimer, N.; Seggewiß, J.; Mellmann, A.; Kaspar, U.; Peters, G. Plasmid-encoded transferable mecB-mediated methicillin resistance in Staphylococcus aureus. Emerg. Infect. Dis. 2018, 24, 242–248. [Google Scholar] [CrossRef] [PubMed][Green Version]
  26. Ito, T.; Ma, X.X.; Takeuchi, F.; Okuma, K.; Yuzawa, H.; Hiramatsu, K. Novel type V staphylococcal cassette chromosome mec driven by a novel cassette chromosome recombinase, ccrC. Antimicrob. Agents Chemother. 2004, 48, 2637–2651. [Google Scholar] [CrossRef] [PubMed][Green Version]
  27. Milheiriço, C.; Oliveira, D.C.; de Lencastre, H. Update to the multiplex PCR strategy for assignment of mec element types in Staphylococcus aureus. Antimicrob. Agents Chemother. 2007, 51, 3374–3377. [Google Scholar] [CrossRef] [PubMed][Green Version]
  28. Milheiriço, C.; Oliveira, D.C.; de Lencastre, H. Multiplex PCR strategy for subtyping the staphylococcal cassette chromosome mec type IV in methicillin-resistant Staphylococcus aureus: “SCCmec IV multiplex”. J. Antimicrob. Chemother. 2007, 60, 42–48. [Google Scholar] [CrossRef][Green Version]
  29. Oliveira, D.C.; de Lencastre, H. Methicillin-resistance in Staphylococcus aureus us not affected by the overexpression in trans of the mecA gene repressor: A surprising observation. PLoS ONE 2011, 6, e23287. [Google Scholar] [CrossRef]
  30. Oliveira, D.C.; Tomasz, A.; de Lencastre, H. The evolution of pandemic clones of methicillin-resistant Staphylococcus aureus: Identification of two ancestral genetic backgrounds and the associated mec elements. Microb. Drug Resist. 2001, 7, 349–361. [Google Scholar] [CrossRef]
  31. Oliveira, D.C.; de Lencastre, H. Multiplex PCR strategy for rapid identification of structural types and variants of the mec element in methicillin- resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2002, 46, 2155–2161. [Google Scholar] [CrossRef][Green Version]
  32. Shore, A.C.; Rossney, A.S.; Keane, C.T.; Enright, M.C.; Coleman, D.C. Seven novel variants of the staphylococcal chromosomal cassette mec in methicillin-resistant Staphylococcus aureus isolates from Ireland. Antimicrob. Agents Chemother. 2005, 49, 2070–2083. [Google Scholar] [CrossRef][Green Version]
  33. International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements (IWG-CSCCE). Classification of Staphylococcal cassette chromosome mec (SCCmec): Guidelines for reporting novel SCCmec elements. Antimicrob. Agents Chemother. 2009, 53, 4961–4967. [Google Scholar] [CrossRef][Green Version]
  34. International Working Group on the Classification of Staphylococcal Cassette Chromosome (SCC) Elements (IWG-CSCCE). Available online: (accessed on 3 February 2022).
  35. Urushibara, N.; Paul, S.K.; Hossain, M.A.; Kawaguchiya, M.; Kobayashi, N. Analysis of staphylococcal cassette chromosome mec in Staphylococcus haemolyticus and Staphylococcus sciuri: Identification of a novel ccr gene complex with a newly identified ccrA allotype (ccrA7). Microb. Drug Resist. 2011, 17, 291–297. [Google Scholar] [CrossRef] [PubMed]
  36. Turlej, A.; Hryniewicz, W.; Empel, J. Staphylococcal cassette chromosome mec (SCCmec) classification and typing methods: An overview. Pol. J. Microbiol. 2011, 60, 95–103. [Google Scholar] [CrossRef]
  37. Chongtrakool, P.; Ito, T.; Ma, X.X.; Kondo, Y.; Trakulsomboon, S.; Tiensasitorn, C.; Jamklang, M.; Chavalit, T.; Song, J.H.; Hiramatsu, K. Staphylococcal cassette chromosome mec (SCCmec) typing of methicillin-resistant Staphylococcus aureus strains isolated in 11 Asian countries: A proposal for a new nomenclature for SCCmec elements. Antimicrob. Agents Chemother. 2006, 50, 1001–1012. [Google Scholar] [CrossRef] [PubMed][Green Version]
  38. Katayama, Y.; Ito, T.; Hiramatsu, K. Genetic organization of the chromosome region surrounding mecA in clinical staphylococcal strains: Role of IS431-mediated mecI deletion in expression of resistance in mecA-carrying, low-level methicillin- resistant Staphylococcus haemolyticus. Antimicrob. Agents Chemother. 2001, 45, 1955–1963. [Google Scholar] [CrossRef] [PubMed][Green Version]
  39. Chlebowicz, M.A.; Nganou, K.; Kozytska, S.; Arends, J.P.; Engelmann, S.; Grundmann, H.; Ohlsen, K.; van Dijl, J.M.; Buist, G. Recombination between ccrC genes in a type V (5C2&5) staphylococcal cassette chromosome mec (SCCmec) of Staphylococcus aureus ST398 leads to conversion from methicillin resistance to methicillin susceptibility in vivo. Antimicrob. Agents Chemother. 2010, 54, 783–791. [Google Scholar] [CrossRef][Green Version]
  40. Zong, Z.; Lü, X. Characterization of a new SCCmec element in Staphylococcus cohnii. PLoS ONE 2010, 5, e14016. [Google Scholar] [CrossRef]
  41. Worthing, K.A.; Schwendener, S.; Perreten, V.; Saputra, S.; Coombs, G.W.; Pang, S.; Davies, M.R.; Abraham, S.; Trott, D.J.; Norris, J.M. Characterization of staphylococcal cassette chromosome mec elements from methicillin-resistant Staphylococcus pseudintermedius infections in australian animals. mSphere 2018, 3, e00491-18. [Google Scholar] [CrossRef][Green Version]
  42. Zong, Z.; Peng, C.; Lü, X. Diversity of SCCmec elements in methicillin-resistant coagulase-negative staphylococci clinical isolates. PLoS ONE 2011, 6, e20191. [Google Scholar] [CrossRef]
  43. Ito, T.; Katayama, Y.; Asada, K.; Mori, N.; Tsutsumimoto, K.; Tiensasitorn, C.; Hiramatsu, K. Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2001, 45, 1323–1336. [Google Scholar] [CrossRef][Green Version]
  44. Ma, X.X.; Ito, T.; Tiensasitorn, C.; Jamklang, M.; Chongtrakool, P.; Boyle-Vavra, S.; Daum, R.S.; Hiramatsu, K. Novel type of staphylococcal cassette chromosome mec identified in community-acquired methicillin-resistant Staphylococcus aureus strains. Antimicrob. Agents Chemother. 2002, 46, 1147–1152. [Google Scholar] [CrossRef][Green Version]
  45. Li, S.; Skov, R.L.; Han, X.; Larsen, A.R.; Larsen, J.; Sørum, M.; Wulf, M.; Voss, A.; Hiramatsu, K.; Ito, T. Novel types of staphylococcal cassette chromosome mec elements identified in clonal complex 398 methicillin-resistant Staphylococcus aureus strains. Antimicrob. Agents Chemother. 2011, 55, 3046–3050. [Google Scholar] [CrossRef] [PubMed][Green Version]
  46. Berglund, C.; Ito, T.; Ikeda, M.; Ma, X.X.; Söderquist, B.; Hiramatsu, K. Novel type of staphylococcal cassette chromosome mec in a methicillin-resistant Staphylococcus aureus strain isolated in Sweden. Antimicrob. Agents Chemother. 2008, 52, 3512–3516. [Google Scholar] [CrossRef] [PubMed][Green Version]
  47. Zhang, K.; McClure, J.A.; Elsayed, S.; Conly, J.M. Novel staphylococcal cassette chromosome mec type carrying class a mec and type 4 ccr gene complexes in a canadian epidemic strain of methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2009, 53, 531–540. [Google Scholar] [CrossRef] [PubMed][Green Version]
  48. Wu, Z.; Li, F.; Liu, D.; Xue, H.; Zhao, X. Novel type XII staphylococcal cassette chromosome mec harboring a new cassette chromosome recombinase, CcrC2. Antimicrob. Agents Chemother. 2015, 59, 7597–7601. [Google Scholar] [CrossRef] [PubMed][Green Version]
  49. Baig, S.; Johannesen, T.B.; Overballe-Petersen, S.; Larsen, J.; Larsen, A.R.; Stegger, M. Novel SCCmec type XIII (9A) identified in an ST152 methicillin-resistant Staphylococcus aureus. Infect. Genet. Evol. 2018, 61, 74–76. [Google Scholar] [CrossRef] [PubMed]
  50. Urushibara, N.; Aung, M.S.; Kawaguchiya, M.; Kobayashi, N. Novel staphylococcal cassette chromosome mec (SCCmec) type XIV (5A) and a truncated SCCmec element in SCC composite islands carrying speG in ST5 MRSA in Japan. J. Antimicrob. Chemother. 2020, 75, 46–50. [Google Scholar] [CrossRef]
  51. Oliveira, D.C.; Milheiriço, C.; de Lencastre, H. Redefining a structural variant of staphylococcal cassette chromosome mec, SCCmec type VI. Antimicrob. Agents Chemother. 2006, 50, 3457–3459. [Google Scholar] [CrossRef][Green Version]
  52. Uehara, Y. Current status of staphylococcal cassette chromosome mec (SCCmec). Antibiotics 2022, 11, 86. [Google Scholar] [CrossRef]
  53. Ito, T.; Katayama, Y.; Hiramatsu, K. Cloning and nucleotide sequence determination of the entire mec DNA of pre-methicillin-resistant Staphylococcus aureus N315. Antimicrob. Agents Chemother. 1999, 43, 1449–1458. [Google Scholar] [CrossRef][Green Version]
  54. Kondo, Y.; Ito, T.; Ma, X.X.; Watanabe, S.; Kreiswirth, B.N.; Etienne, J.; Hiramatsu, K. Combination of multiplex PCRs for staphylococcal cassette chromosome mec type assignment: Rapid identification system for mec, ccr, and major differences in junkyard regions. Antimicrob. Agents Chemother. 2007, 51, 264–274. [Google Scholar] [CrossRef][Green Version]
  55. Hisata, K.; Kuwahara-Arai, K.; Yamanoto, M.; Ito, T.; Nakatomi, Y.; Cui, L.; Baba, T.; Terasawa, M.; Sotozono, C.; Kinoshita, S.; et al. Dissemination of methicillin-resistant staphylococci among healthy japanese children. J. Clin. Microbiol. 2005, 43, 3364–3372. [Google Scholar] [CrossRef] [PubMed][Green Version]
  56. Han, X.; Ito, T.; Takeuchi, F.; Ma, X.X.; Takasu, M.; Uehara, Y.; Oliveira, D.C.; de Lencastre, H.; Hiramatsu, K. Identification of a novel variant of staphylococcal cassette chromosome mec, type II.5, and Its truncated form by insertion of putative conjugative transposon Tn6012. Antimicrob. Agents Chemother. 2009, 53, 2616–2619. [Google Scholar] [CrossRef] [PubMed][Green Version]
  57. Berglund, C.; Ito, T.; Ma, X.X.; Ikeda, M.; Watanabe, S.; Soderquist, B.; Hiramatsu, K. Genetic diversity of methicillin-resistant Staphylococcus aureus carrying type IV SCCmec in Orebro county and the western region of Sweden. J. Antimicrob. Chemother. 2009, 63, 32–41. [Google Scholar] [CrossRef] [PubMed]
  58. Kim, J.-S.; Song, W.; Kim, H.-S.; Cho, H.C.; Lee, K.M.; Choi, M.-S.; Kim, E.-C. Association between the methicillin resistance of clinical isolates of Staphylococcus aureus, their staphylococcal cassette chromosome mec (SCCmec) subtype classification, and their toxin gene profiles. Diagn. Microbiol. Infect. Dis. 2006, 56, 289–295. [Google Scholar] [CrossRef]
  59. Kwon, N.H.; Park, K.T.; Moon, J.S.; Jung, W.K.; Kim, S.H.; Kim, J.M.; Hong, S.K.; Koo, H.C.; Joo, Y.S.; Park, Y.H. Staphylococcal cassette chromosome mec (SCCmec) characterization and molecular analysis for methicillin-resistant Staphylococcus aureus and novel SCCmec subtype IVg isolated from bovine milk in Korea. J. Antimicrob. Chemother. 2005, 56, 624–632. [Google Scholar] [CrossRef][Green Version]
  60. Ma, X.X.; Ito, T.; Chongtrakool, P.; Hiramatsu, K. Predom inance of clones carrying Panton-Valentine leukocidin genes among methicillin-resistant Staphylococcus aureus strains isolated in Japanese hospitals from 1979 to 1985. J. Clin. Microbiol. 2006, 44, 4515–4527. [Google Scholar] [CrossRef][Green Version]
  61. Mongkolrattanothai, K.; Boyle, S.; Murphy, T.V.; Daum, R.S. Novel non-mecA-containing staphylococcal chromosomal cassette composite island containing pbp4 and tagF genes in a commensal staphylococcal species: A possible reservoir for antibiotic resistance islands in Staphylococcus aureus. Antimicrob. Agents Chemother. 2004, 48, 1823–1836. [Google Scholar] [CrossRef][Green Version]
  62. Okuma, K.; Iwakawa, K.; Turnidge, J.D.; Grubb, W.B.; Bell, J.M.; O’Brien, F.G.; Coombs, G.W.; Pearman, J.W.; Tenover, F.C.; Kapi, M.; et al. Dissemination of new methicillin-resistant Staphylococcus aureus clones in the community. J. Clin. Microbiol. 2002, 40, 4289–4294. [Google Scholar] [CrossRef][Green Version]
  63. van Hal, S.J.; Steinig, E.J.; Andersson, P.; Holden, M.T.G.; Harris, S.R.; Nimmo, G.R.; Williamson, D.A.; Heffernan, H.; Ritchie, S.R.; Kearns, A.M.; et al. Global scale dissemination of ST93: A divergent Staphylococcus aureus epidemic lineage that has recently emerged from remote northern Australia. Front. Microbiol. 2018, 9, 1453. [Google Scholar] [CrossRef]
  64. Harris, T.M.; Bowen, A.C.; Holt, D.C.; Sarovich, D.S.; Stevens, K.; Currie, B.J.; Howden, B.P.; Carapetis, J.R.; Giffard, P.M.; Tong, S.Y.C. Investigation of trimethoprim/sulfamethoxazole resistance in an emerging sequence type 5 methicillin-resistant Staphylococcus aureus clone reveals discrepant resistance reporting. Clin. Microbiol. Infect. 2018, 24, 1027–1029. [Google Scholar] [CrossRef][Green Version]
  65. Iwao, Y.; Takano, T.; Higuchi, W.; Yamamoto, T. A new staphylococcal cassette chromosome mec IV encoding a novel cell-wall-anchored surface protein in a major ST8 community-acquired methicillin-resistant Staphylococcus aureus clone in Japan. J. Infect. Chemother. 2012, 18, 96–104. [Google Scholar] [CrossRef] [PubMed]
  66. McGuinness, S.L.; Holt, D.C.; Harris, T.M.; Wright, C.; Baird, R.; Giffard, P.M.; Bowen, A.C.; Tong, S.Y.C. Clinical and molecular epidemiology of an emerging Panton-Valentine leukocidin-positive ST5 methicillin-resistant Staphylococcus aureus clone in northern Australia. mSphere 2021, 6, e00651-20. [Google Scholar] [CrossRef] [PubMed]
  67. Hisata, K.; Ito, T.; Jin, J.; Li, S.; Watanabe, S.; Hiramatsu, K.; Matsunaga, N.; Komatsu, M.; Shimizu, T. Dissemination of multiple MRSA clones among community-associated methicillin-resistant Staphylococcus aureus infections from Japanese children with impetigo. J. Infect. Chemother. 2011, 17, 609–621. [Google Scholar] [CrossRef]
  68. Jorgensen, J.H. Mechanisms of methicillin resistance in Staphylococcus aureus and methods for laboratory detections. Infect. Control. Hosp. Epidemiol. 1991, 12, 14–19. [Google Scholar] [CrossRef] [PubMed]
  69. Tomasz, A.; Drugeon, H.B.; de Lencastre, H.M.; Jabes, D.; McDougall, L.; Bille, J. New mechanism for methicillin resistance in Staphylococcus aureus: Clinical isolates that lack the PBP 2a gene and contain normal penicillin-binding proteins with modified penicillin-binding capacity. Antimicrob. Agents Chemother. 1989, 33, 1869–1874. [Google Scholar] [CrossRef] [PubMed][Green Version]
  70. Argudín, M.A.; Roisin, S.; Nienhaus, L.; Dodémont, M.; de Mendonça, R.; Nonhoff, C.; Deplano, A.; Denis, O. Genetic diversity among Staphylococcus aureus isolates showing oxacillin and/or cefoxitin resistance not linked to the presence of mec genes. Antimicrob. Agents Chemother. 2018, 62, e00091-18. [Google Scholar] [CrossRef] [PubMed][Green Version]
  71. Banerjee, R.; Gretes, M.; Harlem, C.; Basuino, L.; Chambers, H.F. A mecA-negative strain of methicillin-resistant Staphylococcus aureus with high-level β-lactam resistance contains mutations in three genes. Antimicrob. Agents Chemother. 2010, 54, 4900–4902. [Google Scholar] [CrossRef][Green Version]
  72. Greninger, A.L.; Chatterjee, S.S.; Chan, L.C.; Hamilton, S.M.; Chambers, H.F.; Chiu, C.Y. Whole-genome sequencing of methicillin-resistant Staphylococcus aureus resistant to fifth-generation cephalosporins reveals potential non-mecA mechanisms of resistance. PLoS ONE 2016, 11, e0149541. [Google Scholar] [CrossRef]
  73. Hodille, E.; Delouere, L.; Bouveyron, C.; Meugnier, H.; Bes, M.; Tristan, A.; Laurent, F.; Vandenesch, F.; Lina, G.; Dumitrescu, O. In vitro activity of ceftobiprole on 440 Staphylococcus aureus strains isolated from bronchopulmonary infections. Med. Mal. Infect. 2017, 47, 152–157. [Google Scholar] [CrossRef]
  74. Morroni, G.; Brenciani, A.; Brescini, L.; Fioriti, S.; Simoni, S.; Pocognoli, A.; Mingoia, M.; Giovanetti, E.; Barchiesi, F.; Giacometti, A.; et al. High rate of ceftobiprole resistance among clinical methicillin-resistant Staphylococcus aureus isolates from a hospital in central Italy. Antimicrob. Agents Chemother. 2018, 62, e01663-18. [Google Scholar] [CrossRef][Green Version]
  75. Liu, W.-T.; Chen, E.-Z.; Yang, L.; Peng, C.; Wang, Q.; Xu, Z.; Chen, D.-Q. Emerging resistance mechanisms for 4 types of common anti-MRSA antibiotics in Staphylococcus aureus: A comprehensive review. Microb. Pathog. 2021, 156, 104915. [Google Scholar] [CrossRef] [PubMed]
  76. Lee, H.; Yoon, E.-J.; Kim, D.; Kim, J.W.; Lee, K.-J.; Kim, H.S.; Kim, Y.R.; Shin, J.H.; Shin, J.H.; Shin, K.S.; et al. Ceftaroline resistance by clone-specific polymorphism in penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2018, 62, e00485-18. [Google Scholar] [CrossRef] [PubMed][Green Version]
  77. Zeng, D.; Debabov, D.; Hartsell, T.L.; Cano, R.J.; Adams, S.; Schuyler, J.A.; McMillan, R.; Pace, J.L. Approved glycopeptide antibacterial drugs: Mechanism of action and resistance. Cold Spring Harb. Perspect. Med. 2016, 6, a026989. [Google Scholar] [CrossRef][Green Version]
  78. Courvalin, P. Vancomycin resistance in gram-positive cocci. Clin. Infect. Dis. 2006, 42, S25–S34. [Google Scholar] [CrossRef] [PubMed]
  79. Novais, C.; Freitas, A.R.; Sousa, J.C.; Baquero, F.; Coque, T.M.; Peixe, L.V. Diversity of Tn1546 and its role in the dissemination of vancomycin-resistant enterococci in Portugal. Antimicrob. Agents Chemother. 2008, 52, 1001–1008. [Google Scholar] [CrossRef] [PubMed][Green Version]
  80. Perichon, B.; Courvalin, P. Heterologous expression of the enterococcal vanA operon in methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2004, 48, 4281–4285. [Google Scholar] [CrossRef][Green Version]
  81. Centers for Disease Control and Prevention. Vancomycin-resistant Staphylococcus aureus--New York, 2004. MMWR Morb. Mortal. Wkly. Rep. 2004, 53, 322–323. [Google Scholar]
  82. Weigel, L.M.; Donlan, R.M.; Shin, D.H.; Jensen, B.; Clark, N.C.; McDougal, L.K.; Zhu, W.; Musser, K.A.; Thompson, J.; Kohlerschmidt, D.; et al. High-level vancomycin-resistant Staphylococcus aureus isolates associated with a polymicrobial biofilm. Antimicrob. Agents Chemother. 2007, 51, 231–238. [Google Scholar] [CrossRef][Green Version]
  83. Weigel, L.M.; Clewell, D.B.; Gill, S.R.; Clark, N.C.; McDougal, L.K.; Flannagan, S.E.; Kolonay, J.F.; Shetty, J.; Killgore, G.E.; Tenover, F.C. Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus. Science 2003, 302, 1569–1571. [Google Scholar] [CrossRef]
  84. Bakthavatchalam, Y.D.; Babu, P.; Munusamy, E.; Dwarakanathan, H.T.; Rupali, P.; Zervos, M.; Victor, P.J.; Veeraraghavan, B. Genomic insights on heterogeneous resistance to vancomycin and teicoplanin in methicillin-resistant Staphylococcus aureus: A first report from South India. PLoS ONE 2019, 14, e0227009. [Google Scholar] [CrossRef][Green Version]
  85. Szymanek-Majchrzak, K.; Mlynarczyk, A.; Mlynarczyk, G. Characteristics of glycopeptide-resistant Staphylococcus aureus strains isolated from inpatients of three teaching hospitals in Warsaw, Poland. Antimicrob. Resist. Infect. Control 2018, 7, 105. [Google Scholar] [CrossRef] [PubMed]
  86. Zhang, S.; Sun, X.; Chang, W.; Dai, Y.; Ma, X. Systematic review and meta-analysis of the epidemiology of vancomycin-intermediate and heterogeneous vancomycin-intermediate Staphylococcus aureus isolates. PLoS ONE 2015, 10, e0136082. [Google Scholar] [CrossRef] [PubMed]
  87. Sakurada, M.; Sumi, H.; Kaji, K.; Kobayashi, N.; Sakai, Y.; Aung, M.S.; Urushibara, N. Pacemaker-associated infection caused by ST81/SCCmec IV methicillin-resistant, vancomycin-intermediate Staphylococcus aureus in Japan. New Microbes New Infect. 2020, 35, 100656. [Google Scholar] [CrossRef]
  88. Katayama, Y.; Sekine, M.; Hishinuma, T.; Aiba, Y.; Hiramatsu, K. Complete reconstitution of the vancomycin-intermediate Staphylococcus aureus phenotype of strain Mu50 in vancomycin-susceptible S. aureus. Antimicrob. Agents Chemother. 2016, 60, 3730–3742. [Google Scholar] [CrossRef] [PubMed][Green Version]
  89. Kim, J.W.; Lee, K.J. Single-nucleotide polymorphisms in a vancomycin-resistant Staphylococcus aureus strain based on whole-genome sequencing. Arch. Microbiol. 2020, 202, 2255–2261. [Google Scholar] [CrossRef]
  90. Picazo, J.J.; Betriu, C.; Culebras, E.; Rodríguez-Avial, I.; Gómez, M.; López-Fabal, F.; Vira, G. Methicillin-resistant Staphylococcus aureus: Changes in the susceptibility pattern to daptomycin during a 10-year period (2001–2010). Rev. Esp. Quimioter. 2011, 24, 107–111. [Google Scholar]
  91. Jansen, A.; Türck, M.; Szekat, C.; Nagel, M.; Clever, I.; Bierbaum, G. Role of insertion elements and yycFG in the development of decreased susceptibility to vancomycin in Staphylococcus aureus. Int. J. Med. Microbiol. 2007, 297, 205–215. [Google Scholar] [CrossRef]
  92. Młynarczyk, G.; Młynarczyk, A.; Zabicka, D.; Jeljaszewicz, J. Lysogenic conversion as a factor influencing the vancomycin tolerance phenomenon in Staphylococcus aureus. J. Antimicrob. Chemother. 1997, 40, 136–137. [Google Scholar] [CrossRef][Green Version]
  93. Colca, J.R.; McDonald, W.G.; Waldon, D.J.; Thomasco, L.M.; Gadwood, R.C.; Lund, E.T.; Cavey, G.S.; Mathews, W.R.; Adams, L.D.; Cecil, E.T.; et al. Cross-linking in the living cell locates the site of action of oxazolidinone antibiotics. J. Biol. Chem. 2003, 278, 21972–21979. [Google Scholar] [CrossRef][Green Version]
  94. Shen, T.; Penewit, K.; Waalkes, A.; Xu, L.; Salipante, S.J.; Nath, A.; Werth, B.J. Identification of a novel tedizolid resistance mutation in rpoB of MRSA after in vitro serial passage. J. Antimicrob. Chemother. 2021, 76, 292–296. [Google Scholar] [CrossRef]
  95. Hill, R.L.R.; Kearns, A.M.; Nash, J.; North, S.E.; Pike, R.; Newson, T.; Woodford, N.; Calver, R.; Livermore, D.M. Linezolid-resistant ST36 methicillin-resistant Staphylococcus aureus associated with prolonged linezolid treatment in two paediatric cystic fibrosis patients. J. Antimicrob. Chemother. 2010, 65, 442–445. [Google Scholar] [CrossRef] [PubMed]
  96. Meka, V.G.; Pillai, S.K.; Sakoulas, G.; Wennersten, C.; Venkataraman, L.; DeGirolami, P.C.; Eliopoulos, G.M.; Moellering, R.C., Jr.; Gold, H.S. Linezolid resistance in sequential Staphylococcus aureus isolates associated with a T2500A mutation in the 23S rRNA gene and loss of a single copy of rRNA. J. Infect. Dis. 2004, 190, 311–317. [Google Scholar] [CrossRef] [PubMed][Green Version]
  97. Mendes, R.E.; Deshpande, L.M.; Castanheira, M.; Dipersio, J.; Saubolle, M.; Jones, R.N. First report of cfr-mediated resistance to linezolid in human staphylococcal clinical isolates recovered in the United States. Antimicrob. Agents Chemother. 2008, 52, 2244–2246. [Google Scholar] [CrossRef] [PubMed][Green Version]
  98. Kehrenberg, C.; Aarestrup, F.M.; Schwarz, S. IS21-558 insertion sequences are involved in the mobility of the multiresistance gene cfr. Antimicrob. Agents Chemother. 2007, 51, 483–487. [Google Scholar] [CrossRef] [PubMed][Green Version]
  99. Shore, A.C.; Brennan, O.M.; Ehricht, R.; Monecke, S.; Schwarz, S.; Slickers, P.; Coleman, D.C. Identification and characterization of the multidrug resistance gene cfr in a Panton-Valentine leukocidin-positive sequence type 8 methicillin-resistant Staphylococcus aureus IVa (USA300) isolate. Antimicrob. Agents Chemother. 2010, 54, 4978–4984. [Google Scholar] [CrossRef][Green Version]
  100. Zhu, Y.; Wang, C.; Schwarz, S.; Liu, W.; Yang, Q.; Luan, T.; Wang, L.; Liu, S.; Zhang, W. Identification of a novel tetracycline resistance gene, tet(63), located on a multiresistance plasmid from Staphylococcus aureus. J. Antimicrob. Chemother. 2021, 76, 576–581. [Google Scholar] [CrossRef]
  101. Antonelli, A.; D’Andrea, M.M.; Brenciani, A.; Galeotti, C.L.; Morroni, G.; Pollini, S.; Varaldo, P.E.; Rossolini, G.M. Characterization of poxtA, a novel phenicol-oxazolidinone-tetracycline resistance gene from an MRSA of clinical origin. J. Antimicrob. Chemother. 2018, 73, 1763–1769. [Google Scholar] [CrossRef][Green Version]
  102. Venugopal, A.A.; Johnson, S. Fidaxomicin: A novel macrocyclic antibiotic approved for treatment of Clostridium difficile infection. Clin. Infect. Dis. 2012, 54, 568–574. [Google Scholar] [CrossRef][Green Version]
  103. Mlynarczyk, B.; Mlynarczyk, A.; Kmera-Muszynska, M.; Majewski, S.; Mlynarczyk, G. Mechanisms of resistance to antimicrobial drugs in pathogenic Gram-positive cocci. Mini Rev. Med. Chem. 2010, 10, 928–937. [Google Scholar] [CrossRef]
  104. Weisblum, B. Macrolide resistance. Drug Resist. Update 1998, 1, 29–41. [Google Scholar] [CrossRef]
  105. Chen, L.; Mediavilla, J.R.; Smyth, D.S.; Chavda, K.D.; Ionescu, R.; Roberts, R.B.; Robinson, D.A.; Kreiswirth, B.N. Identification of a novel transposon (Tn6072) and a truncated staphylococcal cassette chromosome mec element in methicillin-resistant Staphylococcus aureus ST239. Antimicrob. Agents Chemother. 2010, 54, 3347–3354. [Google Scholar] [CrossRef] [PubMed][Green Version]
  106. Horinouchi, S.; Weisblum, B. Nucleotide sequence and functional map of pE194, a plasmid that specifies inducible resistance to macrolide, lincosamide, and streptogramin type B antibodies. J. Bacteriol. 1982, 150, 804–814. [Google Scholar] [CrossRef] [PubMed][Green Version]
  107. Catchpole, I.; Thomas, C.; Davies, A.; Dyke, K.G. The nucleotide sequence of Staphylococcus aureus plasmid pT48 conferring inducible macrolide-lincosamide-streptogramin B resistance and comparison with similar plasmids expressing constitutive resistance. Microbiology 1988, 134, 697–709. [Google Scholar] [CrossRef][Green Version]
  108. Projan, S.J.; Monod, M.; Narayanan, C.S.; Dubnau, D. Replication properties of pIM13, a naturally occurring plasmid found in Bacillus subtilis, and of its close relative pE5, a plasmid native to Staphylococcus aureus. J. Bacteriol. 1987, 169, 5131–5139. [Google Scholar] [CrossRef][Green Version]
  109. Oliveira, S.S.; Murphy, E.; Gamon, M.R.; Bastos, M.C. pRJ5: A naturally occurring Staphylococcus aureus plasmid expressing constitutive macrolide-lincosamide-streptogramin B resistance contains a tandem duplication in the leader region of the ermC gene. J. Gen. Microbiol. 1993, 139, 1461–1467. [Google Scholar] [CrossRef][Green Version]
  110. Catchpole, I.; Dyke, K.G.H. A Staphylococcus aureus plasmid that specifies constitutive macrolide-lincosamide-streptogramin B resistance contains a novel deletion in the ermC attenuator. FEMS Microbiol. Lett. 1990, 69, 43–48. [Google Scholar] [CrossRef]
  111. Needham, C.; Noble, W.C.; Dyke, K.G. The staphylococcal insertion sequence IS257 is active. Plasmid 1995, 34, 198–205. [Google Scholar] [CrossRef]
  112. Diep, B.A.; Carleton, H.A.; Chang, R.F.; Sensabaugh, G.F.; Perdreau-Remington, F. Roles of 34 virulence genes in the evolution of hospital- and community-associated strains of methicillin-resistant Staphylococcus aureus. J. Infect. Dis. 2006, 193, 1495–1503. [Google Scholar] [CrossRef][Green Version]
  113. Steward, C.D.; Raney, P.M.; Morrell, A.K.; Williams, P.P.; McDougal, L.K.; Jevitt, L.; McGowan, J.E., Jr.; Tenover, F.C. Testing for induction of clindamycin resistance in erythromycin-resistant isolates of Staphylococcus aureus. J. Clin. Microbiol. 2005, 43, 1716–1721. [Google Scholar] [CrossRef][Green Version]
  114. Malhotra-Kumar, S.; Mazzariol, A.; Van Heirstraeten, L.; Lammens, C.; de Rijk, P.; Cornaglia, G.; Goossens, H. Unusual resistance patterns in macrolide-resistant Streptococcus pyogenes harbouring erm(A). J. Antimicrob. Chemother. 2009, 63, 42–46. [Google Scholar] [CrossRef][Green Version]
  115. Matsuoka, M.; Inoue, M.; Nakajima, Y.; Endo, Y. New erm gene in Staphylococcus aureus clinical isolates. Antimicrob. Agents Chemother. 2002, 46, 211–215. [Google Scholar] [CrossRef][Green Version]
  116. Argudín, M.A.; Tenhagen, B.-A.; Fetsch, A.; Sachsenröder, J.; Käsbohrer, A.; Schroeter, A.; Hammerl, J.A.; Hertwig, S.; Helmuth, R.; Bräunig, J.; et al. Virulence and resistance determinants of German Staphylococcus aureus ST398 isolates from nonhuman sources. Appl. Environ. Microbiol. 2011, 77, 3052–3060. [Google Scholar] [CrossRef] [PubMed][Green Version]
  117. Takano, T.; Higuchi, W.; Otsuka, T.; Baranovich, T.; Enany, S.; Saito, K.; Isobe, H.; Dohmae, S.; Ozaki, K.; Takano, M.; et al. Novel characteristics of community-acquired methicillin-resistant Staphylococcus aureus strains belonging to multilocus sequence type 59 in Taiwan. Antimicrob. Agents Chemother. 2008, 52, 837–845. [Google Scholar] [CrossRef] [PubMed][Green Version]
  118. Luna, V.A.; Heiken, M.; Judge, K.; Ulep, C.; Van Kirk, N.; Luis, H.; Bernardo, M.; Leitao, J.; Roberts, M.C. Distribution of mef(A) in gram-positive bacteria from healthy portuguese children. Antimicrob. Agents Chemother. 2002, 46, 2513–2517. [Google Scholar] [CrossRef] [PubMed][Green Version]
  119. Lozano, C.; Aspiroz, C.; Ara, M.; Gómez-Sanz, E.; Zarazaga, M.; Torres, C. Methicillin-resistant Staphylococcus aureus (MRSA) ST398 in a farmer with skin lesions and in pigs of his farm: Clonal relationship and detection of lnu(A) gene. Clin. Microbiol. Infect. 2011, 17, 923–927. [Google Scholar]
  120. Lozano, C.; Rezusta, A.; Gómez, P.; Gómez-Sanz, E.; Báez, N.; Martin-Saco, G.; Zarazaga, M.; Torres, C. High prevalence of spa types associated with the clonal lineage CC398 among tetracycline-resistant methicillin-resistant Staphylococcus aureus strains in a Spanish hospital. J. Antimicrob. Chemother. 2012, 67, 330–334. [Google Scholar] [CrossRef][Green Version]
  121. Schmitz, F.J.; Petridou, J.; Fluit, A.C.; Hadding, U.; Peters, G.; von Eiff, C. Distribution of macrolide-resistance genes in Staphylococcus aureus blood-culture isolates from fifteen german university hospitals. Eur. J. Clin. Microbiol. Infect. Dis. 2000, 19, 385–387. [Google Scholar] [CrossRef]
  122. Schmitz, F.-J.; Sadurski, R.; Kray, A.; Boos, M.; Geisel, R.; Köhrer, K.; Verhoef, J.; Fluit, A.C. Prevalence of macrolide-resistance genes in Staphylococcus aureus and Enterococcus faecium isolates from 24 European university hospitals. J. Antimicrob. Chemother. 2000, 45, 891–894. [Google Scholar] [CrossRef][Green Version]
  123. Cassone, M.; D’Andrea, M.M.; Iannelli, F.; Oggioni, M.R.; Rossolini, G.M.; Pozzi, G. DNA microarray for detection of macrolide resistance genes. Antimicrob. Agents Chemother. 2006, 50, 2038–2041. [Google Scholar] [CrossRef][Green Version]
  124. Qin, X.; Poon, B.; Kwong, J.; Niles, D.; Schmidt, B.Z.; Rajagopal, L.; Gantt, S. Two paediatric cases of skin and soft-tissue infections due to clindamycin-resistant Staphylococcus aureus carrying a plasmid-encoded vga(A) allelic variant for a putative efflux pump. Int. J. Antimicrob. Agents 2011, 38, 81–83. [Google Scholar] [CrossRef]
  125. Wang, B.; Xu, Y.; Zhao, H.; Wang, X.; Rao, L.; Guo, Y.; Yi, X.; Hu, L.; Chen, S.; Han, L.; et al. Methicillin-resistant Staphylococcus aureus in China: A multicenter longitudinal study and whole-genome sequencing. Emerg. Microbes Infect. 2022, 11, 532–542. [Google Scholar] [CrossRef] [PubMed]
  126. Schnellmann, C.; Gerber, V.; Rossano, A.; Jaquier, V.; Panchaud, Y.; Doherr, M.G.; Thomann, A.; Straub, R.; Perreten, V. Presence of new mecA and mph(C) variants conferring antibiotic resistance in Staphylococcus spp. isolated from the skin of horses before and after clinic admission. J. Clin. Microbiol. 2006, 44, 4444–4454. [Google Scholar] [CrossRef] [PubMed][Green Version]
  127. Loeza-Lara, P.D.; Soto-Huipe, M.; Baizabal-Aguirre, V.M.; Ochoa-Zarzosa, A.; Valdez-Alarcón, J.J.; Cano-Camacho, H.; López-Meza, J.E. pBMSa1, a plasmid from a dairy cow isolate of Staphylococcus aureus, encodes a lincomycin resistance determinant and replicates by the rolling-circle mechanism. Plasmid 2004, 52, 48–56. [Google Scholar] [CrossRef] [PubMed]
  128. Luthje, P.; Schwarz, S. Molecular basis of resistance to macrolides and lincosamides among staphylococci and streptococci from various animal sources collected in the resistance monitoring program BfT-Germ. Vet. Int. J. Antimicrob. Agents 2007, 29, 528–535. [Google Scholar] [CrossRef]
  129. Wondrack, L.; Massa, M.; Yang, B.V.; Sutcliffe, J. Clinical strain of Staphylococcus aureus inactivates and causes efflux of macrolides. Antimicrob. Agents Chemother. 1996, 40, 992–998. [Google Scholar] [CrossRef][Green Version]
  130. Allignet, J.; Liassine, N.; El Solh, N. Characterization of a staphylococcal plasmid related to pUB110 and carrying two novel genes, vatC and vgbB, encoding resistance to streptogramins A and B and similar antibiotics. Antimicrob. Agents Chemother. 1998, 42, 1794–1798. [Google Scholar] [CrossRef][Green Version]
  131. Haroche, J.; Morvan, A.; Davi, M.; Allignet, J.; Bimet, F.; El Solh, N. Clonal diversity among streptogramin A-resistant Staphylococcus aureus isolates collected in french hospitals. J. Clin. Microbiol. 2003, 41, 586–591. [Google Scholar] [CrossRef][Green Version]
  132. Mukhtar, T.A.; Koteva, K.P.; Hughes, D.W.; Wright, G.D. Vgb from Staphylococcus aureus inactivates streptogramin B antibiotics by an elimination mechanism not hydrolysis. Biochemistry 2001, 40, 8877–8886. [Google Scholar] [CrossRef]
  133. Malbruny, B.; Canu, A.; Bozdogan, B.; Fantin, B.; Zarrouk, V.; Dutka-Malen, S.; Feger, C.; Leclercq, R. Resistance to quinupristin-dalfopristin due to mutation of L22 ribosomal protein in Staphylococcus aureus. Antimicrob. Agents Chemother. 2002, 46, 2200–2207. [Google Scholar] [CrossRef][Green Version]
  134. Prunier, A.L.; Trong, H.N.; Tande, D.; Segond, C.; Leclercq, R. Mutation of L4 ribosomal protein conferring unusual macrolide resistance in two independent clinical isolates of Staphylococcus aureus. Microb. Drug Resist. 2005, 11, 18–20. [Google Scholar] [CrossRef]
  135. Chandrakanth, R.; Raju, S.; Patil, S.A. Aminoglycoside-resistance mechanisms in multidrug-resistant Staphylococcus aureus clinical isolates. Curr. Microbiol. 2008, 56, 558–562. [Google Scholar] [CrossRef] [PubMed]
  136. Emaneini, M.; Taherikalani, M.; Eslampour, M.A.; Sedaghat, H.; Aligholi, M.; Jabalameli, F.; Shahsavan, S.; Sotoudeh, N. Phenotypic and genotypic evaluation of aminoglycoside resistance in clinical isolates of staphylococci in Tehran, Iran. Microb. Drug Resist. 2009, 15, 129–132. [Google Scholar] [CrossRef] [PubMed]
  137. Rossolini, G.M.; Mantengoli, E. Antimicrobial resistance in Europe and its potential impact on empirical therapy. Clin. Microbiol. Infect. 2008, 14, 2–8. [Google Scholar] [CrossRef][Green Version]
  138. Clark, J.A.; Burgess, D.S. Plazomicin: A new aminoglycoside in the fight against antimicrobial resistance. Ther. Adv. Infect. Dis. 2020, 7, 2049936120952604. [Google Scholar] [CrossRef] [PubMed]
  139. Melter, O.; Radojevič, B. Small colony variants of Staphylococcus aureus—Review. Folia Microbiol. 2010, 55, 548–558. [Google Scholar] [CrossRef] [PubMed]
  140. Ardic, N.; Sareyyupoglu, B.; Ozyurt, M.; Haznedaroglu, T.; Ilga, U. Investigation of aminoglycoside modifying enzyme genes in methicillin-resistant staphylococci. Microbiol. Res. 2006, 161, 49–54. [Google Scholar] [CrossRef]
  141. Ida, T.; Okamoto, R.; Shimauchi, C.; Okubo, T.; Kuga, A.; Inoue, M. Identification of aminoglycoside-modifying enzymes by susceptibility testing: Epidemiology of methicillin-resistant Staphylococcus aureus in Japan. J. Clin. Microbiol. 2001, 39, 3115–3121. [Google Scholar] [CrossRef][Green Version]
  142. Raju, S.; Oli, A.K.; Patil, S.A.; Chandrakanth, R.K. Prevalence of multidrug-resistant Staphylococcus aureus in diabetics clinical samples. World J. Microbiol. Biotechnol. 2010, 26, 171–176. [Google Scholar] [CrossRef]
  143. Yadegar, A.; Sattari, M.; Mozafari, N.A.; Goudarzi, G.R. Prevalence of the genes encoding aminoglycoside-modifying enzymes and methicillin resistance among clinical isolates of Staphylococcus aureus in Tehran, Iran. Microb. Drug Resist. 2009, 15, 109–113. [Google Scholar] [CrossRef]
  144. Szymanek-Majchrzak, K.; Mlynarczyk, A.; Kawecki, D.; Pacholczyk, M.; Durlik, M.; Deborska-Materkowska, D.; Paczek, L.; Mlynarczyk, G. Resistance to aminoglycosides of methicillin-resistant strains of Staphylococcus aureus, originating in the surgical and transplantation wards of the Warsaw clinical center—A retrospective analysis. Transplant. Proc. 2018, 50, 2170–2175. [Google Scholar] [CrossRef]
  145. Lowy, D. Antimicrobial resistance: The example of Staphylococcus aureus. J. Clin. Investig. 2003, 111, 1265–1273. [Google Scholar] [CrossRef] [PubMed]
  146. Ida, T.; Okamoto, R.; Nonoyama, M.; Irinoda, K.; Kurazono, M.; Inoue, M. Antagonism between aminoglycosides and beta-lactams in a methicillin-resistant Staphylococcus aureus isolate involves induction of an aminoglycoside-modifying enzyme. Antimicrob. Agents Chemother. 2002, 46, 1516–1521. [Google Scholar] [CrossRef] [PubMed][Green Version]
  147. Fujimura, S.; Tokue, Y.; Takahashi, H.; Kobayashi, T.; Gomi, K.; Abe, T.; Nukiwa, T.; Watanabe, A. Novel arbekacin- and amikacin-modifying enzyme of methicillin-resistant Staphylococcus aureus. FEMS Microbiol. Lett. 2000, 190, 299–303. [Google Scholar] [CrossRef]
  148. Derbise, A.; de Cespedes, G.; El Solh, N. Nucleotide sequence of the Staphylococcus aureus transposon, Tn5405, carrying aminoglycosides resistance genes. J. Basic Microbiol. 1997, 37, 379–384. [Google Scholar] [CrossRef]
  149. Derbise, A.; Dyke, K.G.; El Solh, N. Characterization of a Staphylococcus aureus transposon, Tn5405, located within Tn5404 and carrying the aminoglycoside resistance genes, aphA-3 and aadE. Plasmid 1996, 35, 174–188. [Google Scholar] [CrossRef] [PubMed]
  150. Xu, Z.; Li, L.; Shirtliff, M.E.; Peters, B.M.; Li, B.; Peng, Y.; Alam, M.J.; Yamasaki, S.; Shi, L. Resistance class 1 integron in clinical methicillin-resistant Staphylococcus aureus strains in southern China, 2001–2006. Clin. Microbiol. Infect. 2011, 17, 714–718. [Google Scholar] [CrossRef] [PubMed][Green Version]
  151. Ding, Y.; Onodera, Y.; Lee, J.C.; Hooper, D.C. NorB, an efflux pump in Staphylococcus aureus strain MW2, contributes to bacterial fitness in abscesses. J. Bacteriol. 2008, 190, 7123–7129. [Google Scholar] [CrossRef] [PubMed][Green Version]
  152. Cheng, J.; Thanassi, J.A.; Thoma, C.L.; Bradbury, B.J.; Deshpande, M.; Pucci, M.J. Dual targeting of DNA gyrase and topoisomerase IV: Target interactions of heteroaryl isothiazolones in Staphylococcus aureus. Antimicrob. Agents Chemother. 2007, 51, 2445–2453. [Google Scholar] [CrossRef][Green Version]
  153. Hooper, D.C. Mechanisms of quinolone resistance. In Gram-Positive Pathogens; Fischetti, V.A., Novick, R.P., Ferretti, J.J., Portnoy, D.A., Rood, J.I., Eds.; ASM Press: Washington, WA, USA, 2006; pp. 821–833. [Google Scholar]
  154. Guay, G.G.; Khan, S.A.; Rothstein, D.M. The tet(K) gene of plasmid pT181 of Staphylococcus aureus encodes an efflux protein that contains 14 transmembrane helices. Plasmid 1993, 30, 163–166. [Google Scholar] [CrossRef]
  155. Noguchi, N.; Aoki, T.; Sasatsu, M.; Kono, M.; Shishido, K.; Ando, T. Determination of the complete nucleotide sequence of pNS1, a staphylococcal tetracycline-resistance plasmid propagated in Bacillus subtilis. FEMS Microbiol. Lett. 1986, 37, 283–288. [Google Scholar] [CrossRef]
  156. Moon, K.H.; Kim, W.K.; Yoon, S.J.; Kim, M.; Shin, C.K.; Im, S.H. Association of tet gene with partial sequence of IS431mec in tetracycline resistance plasmid pKH1. Arch. Pharmacal Res. 1996, 19, 171–172. [Google Scholar]
  157. Truong-Bolduc, Q.C.; Dunman, P.M.; Strahilevitz, J.; Projan, S.J.; Hooper, D.C. MgrA is a multiple regulator of two new efflux pumps in Staphylococcus aureus. J. Bacteriol. 2005, 187, 2395–2405. [Google Scholar] [CrossRef][Green Version]
  158. Trzciński, K.; Cooper, B.S.; Hryniewicz, W.; Dowson, C.G. Expression of resistance to tetracyclines in strains of methicillin-resistant Staphylococcus aureus. J. Antimicrob. Chemother. 2000, 45, 763–770. [Google Scholar] [CrossRef][Green Version]
  159. McDougal, L.K.; Fosheim, G.E.; Nicholson, A.; Bulens, S.N.; Limbago, B.M.; Shearer, J.E.; Summers, A.O.; Patel, J.B. Emergence of resistance among USA300 methicillin-resistant Staphylococcus aureus isolates causing invasive disease in the United States. Antimicrob. Agents Chemother. 2010, 54, 3804–3811. [Google Scholar] [CrossRef][Green Version]
  160. De Vries, L.E.; Christensen, H.; Skov, R.L.; Aarestrup, F.M.; Agersø, Y. Diversity of the tetracycline resistance gene tet(M) and identification of Tn916- and Tn5801-like (Tn6014) transposons in Staphylococcus aureus from humans and animals. J. Antimicrob. Chemother. 2009, 64, 490–500. [Google Scholar] [CrossRef] [PubMed][Green Version]
  161. Dyke, K.G.H.; Curnock, S.P.; Golding, M.; Noble, W.C. Cloning of the gene conferring resistance to mupirocin in Staphylococcus aureus FEMS Microbiol. Lett. 1991, 77, 195–198. [Google Scholar]
  162. Yoo, J.I.; Shin, E.S.; Chung, G.T.; Lee, K.M.; Yoo, J.S.; Lee, Y.S. Restriction fragment length polymorphism (RFLP) patterns and sequence analysis of high-level mupirocin-resistant meticillin-resistant staphylococci. Int. J. Antimicrob. Agents 2010, 35, 50–55. [Google Scholar] [CrossRef] [PubMed]
  163. Cadilla, A.; David, M.Z.; Daum, R.S.; Boyle-Vavra, S. Association of high-level mupirocin resistance and multi-drug resistant methicillin-resistant Staphylococcus aureus at an academic center in the midwestern United States. J. Clin. Microbiol. 2011, 49, 95–100. [Google Scholar] [CrossRef][Green Version]
  164. Caffrey, A.R.; Quilliam, B.J.; LaPlante, K.L. Risk factors associated with mupirocin resistance in meticillin-resistant Staphylococcus aureus. J. Hosp. Infect. 2010, 76, 206–210. [Google Scholar] [CrossRef]
  165. Perez-Roth, E.; Kwong, S.M.; Alcoba-Florez, J.; Firth, N.; Mendez-Alvarez, S. Complete nucleotide sequence and comparative analysis of pPR9, a 41.7-kilobase conjugative staphylococcal multiresistance plasmid conferring high-level mupirocin resistance. Antimicrob. Agents Chemother. 2010, 54, 2252–2257. [Google Scholar] [CrossRef][Green Version]
  166. Rasmussen, A.K.; Skov, R.L.; Venezia, R.A.; Johnson, J.K.; Stender, H. Evaluation of mupA EVIGENE assay for determination of high-level mupirocin resistance in Staphylococcus aureus. J. Clin. Microbiol. 2010, 48, 4253–4255. [Google Scholar] [CrossRef] [PubMed][Green Version]
  167. Seah, C.; Alexander, D.C.; Louie, L.; Simor, A.; Low, D.E.; Longtin, J.; Melano, R.G. MupB, a new high-level mupirocin resistance mechanism in Staphylococcus aureus. Antimicrob. Agents Chemother. 2012, 56, 1916–1920. [Google Scholar] [CrossRef] [PubMed][Green Version]
  168. Hurdle, J.G.; O’Neill, A.J.; Chopra, I. The isoleucyl-tRNA synthetase mutation V588F conferring mupirocin resistance in glycopeptide-intermediate Staphylococcus aureus is not associated with a significant fitness burden. J. Antimicrob. Chemother. 2004, 53, 102–104. [Google Scholar] [CrossRef] [PubMed]
  169. Lannergard, J.; Norstrom, T.; Hughes, D. Genetic determinants of resistance to fusidic acid among clinical bacteremia isolates of Staphylococcus aureus. Antimicrob. Agents Chemother. 2009, 53, 2059–2065. [Google Scholar] [CrossRef][Green Version]
  170. Mairi, A.; Touati, A.; Pantel, A.; Martinez, A.Y.; Ahmim, M.; Sotto, A.; Dunyach-Remy, C.; Lavigne, J.P. First report of CC5-MRSA-IV-SCCfus “maltese clone” in Bat Guano. Microorganisms 2021, 9, 2264. [Google Scholar] [CrossRef]
  171. Lacey, R.W.; Rosdahl, V.T. An unusual “penicillinase plasmid” in Staphylococcus aureus; evidence for its transfer under natural conditions. J. Med. Microbiol. 1974, 7, 1–9. [Google Scholar] [CrossRef][Green Version]
  172. O’Brien, F.G.; Price, C.; Grubb, W.B.; Gustafson, J.E. Genetic characterization of the fusidic acid and cadmium resistance determinants of Staphylococcus aureus plasmid pUB101. J. Antimicrob. Chemother. 2002, 50, 313–321. [Google Scholar] [CrossRef][Green Version]
  173. O’Neill, A.J.; Chopra, I. Molecular basis of fusB-mediated resistance to fusidic acid in Staphylococcus aureus. Mol. Microbiol. 2006, 59, 664–676. [Google Scholar] [CrossRef]
  174. O’Neill, A.J.; Larsen, A.R.; Skov, R.; Henriksen, A.S.; Chopra, I. Characterization of the epidemic european fusidic acid-resistant impetigo clone of Staphylococcus aureus. J. Clin. Microbiol. 2007, 45, 1505–1510. [Google Scholar] [CrossRef][Green Version]
  175. Mehta, S.; Cuirolo, A.X.; Plata, K.B.; Riosa, S.; Silverman, J.A.; Rubio, A.; Rosato, R.R.; Rosato, A.E. VraSR two-component regulatory system contributes to mprF-mediated decreased susceptibility to daptomycin in in vivo-selected clinical strains of methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2012, 56, 92–102. [Google Scholar] [CrossRef][Green Version]
  176. Yang, S.J.; Kreiswirth, B.N.; Sakoulas, G.; Yeaman, M.R.; Xiong, Y.Q.; Sawa, A.; Bayer, A.S. Enhanced expression of dltABCD is associated with the development of daptomycin nonsusceptibility in a clinical endocarditis isolate of Staphylococcus aureus. J. Infect. Dis. 2009, 200, 1916–1920. [Google Scholar] [CrossRef] [PubMed][Green Version]
  177. Yang, S.J.; Xiong, Y.Q.; Dunman, P.M.; Schrenzel, J.; Franc, P.; Peschel, A.; Bayer, A.S. Regulation of mprF in daptomycin-nonsusceptible Staphylococcus aureus strains. Antimicrob. Agents Chemother. 2009, 53, 2636–2637. [Google Scholar] [CrossRef] [PubMed][Green Version]
  178. Müller, A.; Grein, F.; Otto, A.; Gries, K.; Orlov, D.; Zarubaev, V.; Girard, M.; Sher, X.; Shamova, O.; Roemer, T.; et al. Differential daptomycin resistance development in Staphylococcus aureus strains with active and mutated gra regulatory systems. Int. J. Med. Microbiol. 2018, 308, 335–348. [Google Scholar] [CrossRef]
  179. Allignet, J.; Loncle, V.; Simenel, C.; Delepierre, M.; El Solh, N. Sequence of a staphylococcal gene, vat, encoding an acetyltransferase inactivating the A-type compounds of virginiamycin-like antibiotics. Gene 1993, 130, 91–98. [Google Scholar] [CrossRef]
  180. Allignet, J.; El Solh, N. Diversity among the gram-positive acetyltransferases inactivating streptogramin A and structurally related compounds and characterization of a new staphylococcal determinant, vatB. Antimicrob. Agents Chemother. 1995, 39, 2027–2036. [Google Scholar] [CrossRef][Green Version]
  181. Haroche, J.; Allignet, J.; El Solh, N. Tn5406, a new staphylococcal transposon conferring resistance to streptogramin a and related compounds including dalfopristin. Antimicrob. Agents Chemother. 2002, 46, 2337–2343. [Google Scholar] [CrossRef][Green Version]
  182. Haroche, J.; Allignet, J.; Buchrieser, C.; El Solh, N. Characterization of a variant of vga(A) conferring resistance to streptogramin A and related compounds. Antimicrob. Agents Chemother. 2000, 44, 2271–2275. [Google Scholar] [CrossRef][Green Version]
  183. Kadlec, K.; Schwarz, S. Novel ABC transporter gene, vga(C), located on a multiresistance plasmid from a porcine methicillin-resistant Staphylococcus aureus ST398 strain. Antimicrob. Agents Chemother. 2009, 53, 3589–3591. [Google Scholar] [CrossRef][Green Version]
  184. Schwendener, S.; Perreten, V. New transposon Tn6133 in methicillin-resistant Staphylococcus aureus ST398 contains vga(E), a novel streptogramin a, pleuromutilin, and lincosamide resistance gene. Antimicrob. Agents Chemother. 2011, 55, 4900–4904. [Google Scholar] [CrossRef] [PubMed][Green Version]
  185. Allington, D.R.; Rivey, M.P. Quinupristin/dalfopristin: A therapeutic review. Clin. Ther. 2001, 23, 24–44. [Google Scholar] [CrossRef]
  186. Pankuch, G.A.; Jacobs, M.R.; Appelbaum, P.C. Postantibiotic effect and postantibiotic sub-MIC effect of quinupristin-dalfopristin against gram-positive and -negative organisms. Antimicrob. Agents Chemother. 1998, 42, 3028–3031. [Google Scholar] [CrossRef] [PubMed][Green Version]
  187. Aubry-Damon, H.; Soussy, C.J.; Courvalin, P. Characterization of mutations in the rpoB gene that confer rifampin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 1998, 42, 2590–2594. [Google Scholar] [CrossRef] [PubMed][Green Version]
  188. Sekiguchi, J.-I.; Fujino, T.; Araake, M.; Toyota, E.; Kudo, K.; Saruta, K.; Kirikae, T.; Yoshikura, H.; Kuratsuji, T. Emergence of rifampicin resistance in methicillin-resistant Staphylococcus aureus in tuberculosis wards. J. Infect. Chemother. 2006, 12, 47–50. [Google Scholar] [CrossRef] [PubMed]
  189. Schwarz, S.; Witte, D.G. Phenicol resistance. In Frontiers in Antimicrobial Resistance: Atribute to Stuart B. Levy; White, D.G., Alekshun, M.N., McDermott, P.F., Eds.; ASM Press: Washington, WA, USA, 2005; pp. 124–147. [Google Scholar]
  190. Projan, S.J.; Kornblum, J.; Moghazeh, S.L.; Edelman, I.; Gennaro, M.L.; Novick, R.P. Comparative sequence and functional analysis of pT181 and pC221, cognate plasmid replicons from Staphylococcus aureus. Mol. Gen. Genet. 1985, 199, 452–464. [Google Scholar] [CrossRef]
  191. Tennent, J.M.; May, J.W.; Skurray, R.A. Characterisation of chloramphenicol resistance plasmids of Staphylococcus aureus and S. epidermidis by restriction enzyme mapping techniques. J. Med. Microbiol. 1986, 22, 79–84. [Google Scholar] [CrossRef] [PubMed]
  192. Brenner, D.G.; Shaw, W.V. The use of synthetic oligonucleotides with universal templates for rapid DNA sequencing: Results with staphylococcal replicon pC221. EMBO J. 1985, 4, 561–568. [Google Scholar] [CrossRef] [PubMed]
  193. Schwarz, S.; Cardoso, M. Nucleotide sequence and phylogeny of a chloramphenicol acetyltransferase encoded by the plasmid pSCS7 from Staphylococcus aureus. Antimicrob. Agents Chemother. 1991, 35, 1551–1556. [Google Scholar] [CrossRef] [PubMed][Green Version]
  194. Schwarz, S.; Spies, U.; Cardoso, M. Cloning and sequence analysis of a plasmid-encoded chloramphenicol acetyltransferase gene from Staphylococcus intermedius. J. Gen. Microbiol. 1991, 137, 977–981. [Google Scholar] [CrossRef][Green Version]
  195. Smith, M.C.; Thomas, C.D. An accessory protein is required for relaxosome formation by small staphylococcal plasmids. J. Bacteriol. 2004, 186, 3363–3373. [Google Scholar] [CrossRef][Green Version]
  196. Bhakta, M.; Bal, M. Identification and characterization of a shuttle plasmid with antibiotic resistance gene from Staphylococcus aureus. Curr. Microbiol. 2003, 46, 413–417. [Google Scholar] [CrossRef]
  197. Wright, G.D. Bacterial resistance to antibiotics: Enzymatic degradation and modification. Adv. Drug Deliv. Rev. 2005, 57, 1451–1470. [Google Scholar] [CrossRef] [PubMed]
  198. Neoh, H.M.; Cui, L.; Yuzawa, H.; Takeuchi, F.; Matsuo, M.; Hiramatsu, K. Mutated response regulator graR is responsible for phenotypic conversion of Staphylococcus aureus from heterogeneous vancomycin-intermediate resistance to vancomycin-intermediate resistance. Antimicrob. Agents Chemother. 2008, 52, 45–53. [Google Scholar] [CrossRef] [PubMed][Green Version]
  199. Rouch, D.A.; Messerotti, L.J.; Loo, L.S.; Jackson, C.A.; Skurray, R.A. Trimethoprim resistance transposon Tn4003 from Staphylococcus aureus encodes genes for a dihydrofolate reductase and thymidylate synthetase flanked by three copies of IS257. Mol. Microbiol. 1989, 3, 161–175. [Google Scholar] [CrossRef]
  200. Burdeska, A.; Ott, M.; Bannwarth, W.; Then, R.L. Identical genes for trimethoprim-resistant dihydrofolate reductasefrom Staphylococcus aureus in Australia and central Europe. FEBS Lett. 1990, 266, 159–162. [Google Scholar] [CrossRef][Green Version]
  201. Kadlec, K.; Schwarz, S. Identification of a novel trimethoprim resistance gene, dfrK, in a methicillin-resistant Staphylococcus aureus ST398 strain and its physical linkage to the tetracycline resistance gene tet(L). Antimicrob. Agents Chemother. 2009, 53, 776–778. [Google Scholar] [CrossRef] [PubMed][Green Version]
  202. Kadlec, K.; Schwarz, S. Identification of a plasmid-borne resistance gene cluster comprising the resistance genes erm(T), dfrK, and tet(L) in a porcine methicillin-resistant Staphylococcus aureus ST398 strain. Antimicrob. Agents Chemother. 2010, 54, 915–918. [Google Scholar] [CrossRef][Green Version]
  203. Zhao, X.; Chlebowicz-Flissikowska, M.A.; Wang, M.; Murguia, E.V.; de Jong, A.; Becher, D.; Maaß, S.; Buist, G.; van Dijl, J.M. Exoproteomic profiling uncovers critical determinants for virulence of livestock-associated and human-originated Staphylococcus aureus ST398 strains. Virulence 2020, 11, 947–963. [Google Scholar] [CrossRef]
  204. Amdahl, H.; Haapasalo, K.; Tan, L.; Meri, T.; Kuusela, P.I.; van Strijp, J.A.; Rooijakkers, S.; Jokiranta, T.S. Staphylococcal protein Ecb impairs complement receptor-1 mediated recognition of opsonized bacteria. PLoS ONE 2017, 12, e0172675. [Google Scholar] [CrossRef][Green Version]
  205. Lamret, F.; Varin-Simon, J.; Velard, F.; Terryn, C.; Mongaret, C.; Colin, M.; Gangloff, S.C.; Reffuveille, F. Staphylococcus aureus strain-dependent biofilm formation in bone-like environment. Front. Microbiol. 2021, 12, 714994. [Google Scholar] [CrossRef]
  206. Langley, R.J.; Ting, Y.T.; Clow, F.; Young, P.G.; Radcliff, F.J.; Choi, J.M.; Sequeira, R.P.; Holtfreter, S.; Baker, H.; Fraser, J.D. Staphylococcal enterotoxin-like X (SElX) is a unique superantigen with functional features of two major families of staphylococcal virulence factors. PLoS Pathog. 2017, 13, e1006549. [Google Scholar] [CrossRef][Green Version]
  207. Porayath, C.; Suresh, M.K.; Biswas, R.; Nair, B.G.; Mishra, N.; Pal, S. Autolysin mediated adherence of Staphylococcus aureus with fibronectin, gelatin and heparin. Int. J. Biol. Macromol. 2018, 110, 179–184. [Google Scholar] [CrossRef] [PubMed]
  208. Hirschhausen, N.; Schlesier, T.; Peters, G.; Heilmann, C. Characterization of the modular design of the autolysin/adhesin Aaa from Staphylococcus aureus. PLoS ONE 2012, 7, e40353. [Google Scholar] [CrossRef] [PubMed]
  209. Foster, T.J. Surface proteins of Staphylococcus aureus. Microbiol. Spectr. 2019, 7, 4. [Google Scholar] [CrossRef]
  210. Foster, T.J. The MSCRAMM family of cell-wall-anchored surface proteins of gram-positive cocci. Trends Microbiol. 2019, 27, 927–941. [Google Scholar] [CrossRef]
  211. Viela, F.; Speziale, P.; Pietrocola, G.; Dufrêne, Y.F. Bacterial pathogens under high-tension: Staphylococcus aureus adhesion to von Willebrand factor is activated by force. Microb. Cell 2019, 6, 321–323. [Google Scholar] [CrossRef]
  212. Ohnishi, Y.; Okino, N.; Ito, M.; Imayama, S. Ceramidase activity in bacterial skin flora as a possible cause of ceramide deficiency in atopic dermatitis. Clin. Diagn. Lab. Immunol. 1999, 6, 101–104. [Google Scholar] [CrossRef][Green Version]
  213. Pickering, A.C.; Yebra, G.; Gong, X.; Goncheva, M.I.; Wee, B.A.; MacFadyen, A.C.; Muehlbauer, L.F.; Alves, J.; Cartwright, R.A.; Paterson, G.K.; et al. Evolutionary and functional analysis of coagulase positivity among the Staphylococci. mSphere 2021, 6, e0038121. [Google Scholar] [CrossRef]
  214. Courjon, J.; Munro, P.; Benito, Y.; Visvikis, O.; Bouchiat, C.; Boyer, L.; Doye, A.; Lepidi, H.; Ghigo, E.; Lavigne, J.P.; et al. EDIN-B promotes the translocation of Staphylococcus aureus to the bloodstream in the course of pneumonia. Toxins 2015, 7, 4131–4142. [Google Scholar] [CrossRef][Green Version]
  215. Wright, J.A.; Nair, S.P. The lipoprotein components of the Isd and Hts transport systems are dispensable for acquisition of heme by Staphylococcus aureus. FEMS Microbiol. Lett. 2012, 329, 177–185. [Google Scholar] [CrossRef][Green Version]
  216. Conroy, B.S.; Grigg, J.C.; Kolesnikov, M.; Morales, L.D.; Murphy, M.E.P. Staphylococcus aureus heme and siderophore-iron acquisition pathways. BioMetals 2019, 32, 409–424. [Google Scholar] [CrossRef]
  217. Sun, L.; Wu, D.; Chen, Y.; Wang, Q.; Wang, H.; Yu, Y. Characterization of a PVL-negative community-acquired methicillin-resistant Staphylococcus aureus strain of sequence type 88 in China. Int. J. Med. Microbiol. 2017, 307, 346–352. [Google Scholar] [CrossRef] [PubMed]
  218. Uehara, Y.; Sasaki, T.; Baba, T.; Lu, Y.; Imajo, E.; Sato, Y.; Tanno, S.; Furuichi, M.; Kawada, M.; Hiramatsu, K. Regional outbreak of community-associated methicillin-resistant Staphylococcus aureus ST834 in Japanese children. BMC Infect. Dis. 2019, 19, 35. [Google Scholar] [CrossRef] [PubMed]
  219. Heuer, H.; Krogerrecklenfort, E.; Wellington, E.M.; Egan, S.; Elsas, J.D.; Overbeek, L.; Collard, J.M.; Guillaume, G.; Karagouni, A.D.; Nikolakopoulou, T.L.; et al. Gentamicin resistance genes in environmental bacteria: Prevalence and transfer. FEMS Microbiol. Ecol. 2002, 42, 289–302. [Google Scholar] [CrossRef] [PubMed]
  220. Strauß, L.; Stegger, M.; Akpaka, P.E.; Alabi, A.; Breurec, S.; Coombs, G.; Egyir, B.; Larsen, A.R.; Laurent, F.; Monecke, S.; et al. Origin, evolution, and global transmission of community-acquired Staphylococcus aureus ST8. Proc. Natl. Acad. Sci. USA 2017, 114, E10596–E10604. [Google Scholar] [CrossRef] [PubMed][Green Version]
  221. Baig, S.; Larsen, A.R.; Simões, P.M.; Laurent, F.; Johannesen, T.B.; Lilje, B.; Tristan, A.; Schaumburg, F.; Egyir, B.; Cirkovic, I.; et al. Evolution and population dynamics of clonal complex 152 community-associated methicillin-resistant Staphylococcus aureus. mSphere 2020, 5, e00226-20. [Google Scholar] [CrossRef]
  222. Ogura, K.; Kaji, D.; Sasaki, M.; Otsuka, Y.; Takemoto, N.; Miyoshi-Akiyama, T.; Kikuchi, K. Predominance of ST8 and CC1/spa-t1784 methicillin-resistant Staphylococcus aureus isolates in Japan and their genomic characteristics. J. Glob. Antimicrob. Resist. 2022, 28, 195–202. [Google Scholar] [CrossRef]
  223. D’Souza, N.; Rodrigues, C.; Mehta, A. Molecular characterization of methicillin-resistant Staphylococcus aureus with emergence of epidemic clones of sequence type (ST) 22 and ST 772 in Mumbai. J. Clin. Microbiol. 2010, 48, 1806–1811. [Google Scholar] [CrossRef][Green Version]
  224. Broderick, D.; Brennan, G.I.; Drew, R.J.; O’Connell, B. Epidemiological typing of methicillin resistant Staphylococcus aureus recovered from patients attending a maternity hospital in Ireland 2014–2019. Infect. Prev. Pract. 2021, 3, 100124. [Google Scholar] [CrossRef]
  225. Senok, A.; Ehricht, R.; Monecke, S.; Al-Saedan, R.; Somily, A. Molecular characterization of methicillin-resistant Staphylococcus aureus in nosocomial infections in a tertiary-care facility: Emergence of new clonal complexes in Saudi Arabia. New Microbes New Infect. 2016, 14, 13–18. [Google Scholar] [CrossRef][Green Version]
  226. Earls, M.R.; Coleman, D.C.; Brennan, G.I.; Fleming, T.; Monecke, S.; Slickers, P.; Ehricht, R.; Shore, A.C. Intra-hospital, inter-hospital and intercontinental spread of ST78 MRSA from two neonatal intensive care unit outbreaks established using whole-genome sequencing. Front. Microbiol. 2018, 9, 1485. [Google Scholar] [CrossRef]
  227. Kikuta, H.; Shibata, M.; Nakata, S.; Yamanaka, T.; Sakata, H.; Akizawa, K.; Kobayashi, K. Predominant dissemination of PVL-negative CC89 MRSA with SCCmec Type II in children with impetigo in Japan. Int. J. Pediatr. 2011, 2011, 143872. [Google Scholar] [CrossRef] [PubMed][Green Version]
  228. Tristan, A.; Bes, M.; Meugnier, H.; Lina, G.; Bozdogan, B.; Courvalin, P.; Reverdy, M.E.; Enright, M.C.; Vandenesch, F.; Etienne, J. Global distribution of Panton-Valentine leucocidin–positive methicillin-resistant Staphylococcus aureus, 2006. Emerg. Infect. Dis. 2007, 13, 594–600. [Google Scholar] [CrossRef] [PubMed]
  229. Egyir, B.; Guardabassi, L.; Sørum, M.; Nielsen, S.S.; Kolekang, A.; Frimpong, E.; Addo, K.K.; Newman, M.J.; Larsen, A.R. Molecular epidemiology and antimicrobial susceptibility of clinical Staphylococcus aureus from healthcare institutions in Ghana. PLoS ONE 2014, 9, e89716. [Google Scholar] [CrossRef] [PubMed][Green Version]
  230. Monecke, S.; Aamot, H.V.; Stieber, B.; Ruppelt, A.; Ehricht, R. Characterization of PVL-positive MRSA from Norway. APMIS 2014, 122, 580–584. [Google Scholar] [CrossRef] [PubMed]
  231. Jin, Y.; Zhou, W.; Yin, Z.; Zhang, S.; Chen, Y.; Shen, P.; Ji, J.; Chen, W.; Zheng, B.; Xiao, Y. The genetic feature and virulence determinant of highly virulent community-associated MRSA ST338-SCCmec Vb in China. Emerg. Microbes Infect. 2021, 10, 1052–1064. [Google Scholar] [CrossRef]
  232. Boswihi, S.S.; Udo, E.E.; AlFouzan, W. Antibiotic resistance and typing of the methicillin-resistant Staphylococcus aureus clones in Kuwait hospitals, 2016-2017. BMC Microbiol. 2020, 20, 314. [Google Scholar] [CrossRef]
  233. Xiao, M.; Wang, H.; Zhao, Y.; Mao, L.-L.; Brown, M.; Yu, Y.-S.; O’Sullivan, M.V.N.; Kong, F.; Xu, Y.-C. National surveillance of methicillin-resistant Staphylococcus aureus in China highlights a still-evolving epidemiology with 15 novel emerging multilocus sequence types. J. Clin. Microbiol. 2013, 51, 3638–3644. [Google Scholar] [CrossRef][Green Version]
  234. Neradova, K.; Fridrichova, M.; Jakubu, V.; Pomorska, K.; Zemlickova, H. Epidemiological characteristics of methicillin-resistant Staphylococcus aureus isolates from bloodstream cultures at University Hospital in the Czech Republic. Folia Microbiol. 2020, 65, 615–622. [Google Scholar] [CrossRef][Green Version]
  235. Mlynarczyk, A.; Szymanek-Majchrzak, K.; Grzybowska, W.; Durlik, M.; Deborska-Materkowska, D.; Paczek, L.; Chmura, A.; Swoboda-Kopec, E.; Tyski, S.; Mlynarczyk, G. Molecular and phenotypic characteristics of methicillin-resistant Staphylococcus aureus strains isolated from hospitalized patients in transplantation wards. Transplant. Proc. 2014, 46, 2579–2582. [Google Scholar] [CrossRef]
  236. Szymanek-Majchrzak, K.; Mlynarczyk, A.; Dobrzaniecka, K.; Majchrzak, K.; Mierzwinska-Nastalska, E.; Chmura, A.; Kwiatkowski, A.; Durlik, M.; Deborska-Materkowska, D.; Paczek, L.; et al. Epidemiological and drug-resistance types of methicillin-resistant Staphylococcus aureus strains isolated from surgical and transplantation ward patients during 2010 to 2011. Transplant. Proc. 2016, 48, 1414–1417. [Google Scholar] [CrossRef]
  237. Yu, F.; Cienfuegos-Gallet, A.V.; Cunningham, M.H.; Jin, Y.; Wang, B.; Kreiswirth, B.N.; Chen, L. Molecular evolution and adaptation of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) sequence type 9. mSystems 2021, 6, e0049221. [Google Scholar] [CrossRef] [PubMed]
  238. Zhang, T.; Jia, M.; Cheng, Y.; Zhang, W.; Lu, Q.; Guo, Y.; Wen, G.; Shao, H.; Luo, Q. First report of ST9-MRSA-XII from a chicken farm in China. J. Glob. Antimicrob. Resist. 2021, 27, 292–293. [Google Scholar] [CrossRef] [PubMed]
  239. Juhász-Kaszanyitzky, E.; Jánosi, S.; Somogyi, P.; Dán, A.; van der Graaf-van Bloois, L.; van Duijkeren, E.; Wagenaar, J.A. MRSA transmission between cows and humans. Emerg. Infect. Dis. 2007, 13, 630–632. [Google Scholar] [CrossRef]
  240. Hau, S.J.; Kellner, S.; Eberle, K.C.; Waack, U.; Brockmeier, S.L.; Haan, J.S.; Davies, P.R.; Frana, T.; Nicholson, T.L. Methicillin-resistant Staphylococcus aureus sequence type (ST) 5 isolates from health care and agricultural sources adhere equivalently to human keratinocytes. Appl. Environ. Microbiol. 2018, 84, e02073-17. [Google Scholar] [CrossRef] [PubMed][Green Version]
  241. Zou, G.; Matuszewska, M.; Jia, M.; Zhou, J.; Ba, X.; Duan, J.; Zhang, C.; Zhao, J.; Tao, M.; Fan, J.; et al. A survey of chinese pig farms and human healthcare isolates reveals separate human and animal methicillin-resistant Staphylococcus aureus populations. Adv. Sci. 2022, 9, 2103388. [Google Scholar] [CrossRef]
  242. Gómez-Sanz, E.; Torres, C.; Lozano, C.; Fernández-Pérez, R.; Aspiroz, C.; Ruiz-Larrea, F.; Zarazaga, M. Detection, molecular characterization, and clonal diversity of methicillin-resistant Staphylococcus aureus CC398 and CC97 in spanish slaughter pigs of different age groups. Foodborne Pathog. Dis. 2010, 7, 1269–1277. [Google Scholar] [CrossRef]
Figure 1. The most important resistance mechanisms in Staphylococcus aureus: antibiotics Ijms 23 08088 i001, mechanisms of action—green arrows. Resistance to beta lactams: 1. Production of penicillin-binding protein PBP2A, 2. * mutations in PBP genes—rare (MODSA), 3. beta-lactamases production -usually narrow substrate spectrum. Glycopeptide resistance: 4. VanA operon (modification of the antibiotic binding site), Linezolid resistance: 5. adenylyl-N-methyltransferase Cfr-modification 23S rRNA of bacterial ribosome. Resistance to MLS-B (macrolides, lincosamides and streptogramins B): 5. Erm—erythromycin ribosome methylation. Aminoglycosides resistance: 6. antibiotics inactivation by tansferases. Fluoroinolones resistance: 7. mutations in gyrA and gyrB (topoisomerase II) and parC (grlA) and parE (topoisomerase IV) genes (modification of the antibiotic binding site), 8. removal from the bacterial cell by the efflux pump.
Figure 1. The most important resistance mechanisms in Staphylococcus aureus: antibiotics Ijms 23 08088 i001, mechanisms of action—green arrows. Resistance to beta lactams: 1. Production of penicillin-binding protein PBP2A, 2. * mutations in PBP genes—rare (MODSA), 3. beta-lactamases production -usually narrow substrate spectrum. Glycopeptide resistance: 4. VanA operon (modification of the antibiotic binding site), Linezolid resistance: 5. adenylyl-N-methyltransferase Cfr-modification 23S rRNA of bacterial ribosome. Resistance to MLS-B (macrolides, lincosamides and streptogramins B): 5. Erm—erythromycin ribosome methylation. Aminoglycosides resistance: 6. antibiotics inactivation by tansferases. Fluoroinolones resistance: 7. mutations in gyrA and gyrB (topoisomerase II) and parC (grlA) and parE (topoisomerase IV) genes (modification of the antibiotic binding site), 8. removal from the bacterial cell by the efflux pump.
Ijms 23 08088 g001
Figure 2. General scheme of SCCmec cassete.
Figure 2. General scheme of SCCmec cassete.
Ijms 23 08088 g002
Figure 3. Van A operon. IR—inverted repeats, ORF—open reading frame.
Figure 3. Van A operon. IR—inverted repeats, ORF—open reading frame.
Ijms 23 08088 g003
Figure 4. Erm methylase production by S. aureus is regulated at the translational level. RBS—ribosome binding site, M14 and M15—macrolides with a 14- and 15-member ring. (A) In the absence of M14 and M15 macrolides, a leader peptide is produced that attaches to the mRNA preventing translation of the methylase Erm (A,B). When the bacterial ribosome is blocked by macrolides, the leader peptide is not translated and the RNA conformation changes in such a way that methylase poduction is possible.
Figure 4. Erm methylase production by S. aureus is regulated at the translational level. RBS—ribosome binding site, M14 and M15—macrolides with a 14- and 15-member ring. (A) In the absence of M14 and M15 macrolides, a leader peptide is produced that attaches to the mRNA preventing translation of the methylase Erm (A,B). When the bacterial ribosome is blocked by macrolides, the leader peptide is not translated and the RNA conformation changes in such a way that methylase poduction is possible.
Ijms 23 08088 g004
Table 1. The mec gene complexes in S. aureus.
Table 1. The mec gene complexes in S. aureus.
Class of mec Gene Complexmec ComplexSCCmec in S. aureus
AIS431-mecA-mecR1-mecIII, III, VIII, XIII, XIV
BIS431-mecA-ΔmecR1-ΨIS1272I, IV, VI
C1IS431-mecAmecR1-IS431VII, X
C2IS431-mecAmecR1-IS431V, IX, XII
Abbreviations: IS-insertion sequence; IS431 IS431, direct repead orientation of IS; IS431 IS431, inverted repead orientation of IS; Tn, transposon; ΔmecR1, truncated mecI-mecR; blaZ, beta-lactamase gene; Tn4001 (transposon: aacA-aphD, bifunctional acetyltransferase (6′)/phosphotransferase (2″), aminoglycosides resistance determinant).
Table 2. ccr gene comlexes in S. aureus.
Table 2. ccr gene comlexes in S. aureus.
Number of ccr
Gene Complex
Gene of ccrType of SCCmec
1A1B1I, IX
5C1 *V, VII, XIV
* 10 alleles of the C1 gene have been described. In S. aureus, alleles 1, 2, 3, 4, 8, 9 and 10 were described in strains JCSC3624; TSGH17; 85/2082; M; JCSC1435; P1, PM1; ZH47; M06/0171, UMCGM-4. Alleles 5 and 6, were described in S. haemolyticus, allele 7 in S. epidermidis and allele 9 in S. saprophyticus [39,40].
Table 3. Types of SCCmec.
Table 3. Types of SCCmec.
Isolated inGenBank Accession SCCmec
Other Genes and Genetic Elements
No. in SCCmec
I NCTC10442 (JCSC9884)England;1961AB03376334.41 B
II N315 (JCSC9885)Japan; 1981D8693453.02 ApUB110, Tn554
III 85/2082 (JCSC9889)New Zealand; 1985AB03767166.93 ASCCHg, ΨTn554, pT181
IV CA05 (JCSC9890)USA; 1999AB06317224.32 B-
V WIS (JCSC9897) Australia; 1995AB12121927.65C2hsdR, hsdS, hsdM
VI HDE288 (JCSC9900)Portugal; 1996AF41193523.04 B-
VII P5747/2002 (JCSC9900)Sweden; 2002AB37303232.45 C1hsdR, hsdM
VIII C10682 (JCSC9902)Canada; 2003FJ39005732.14 ATn554
IX JCSC6943 (JCSC9903)Thailand; 2006AB50562843.71 C2arsDARBC, cadDX

arsRBC, cadDX
X JCSC6945 (JCSC9904)Canada; 2006AB50563050.87 C1
XI LGA251 (JCSC9905)England; 2007FR82177929.48 EarsRBC, blaZ
XIIBA01611 China; 2015 KR18711149.39C2ΨSCCBA01611
XIII55-99-44 Denmark; 2018 MG67408929.29ATn4001
XIVSC792 (JCSC11500)Japan; 2013–2014LC44064781.55AΨSCCpls; ACME II’; SCCSC640
Abbreviations: pUB110 (plasmid: ant(4′), aminoglycoside resistance; ble, bleomycin resistance); Tn554 (transposon: ermA, rRNA adenine N-6-methyltransferase, MLS-B resistance; spc, O-nucleotydiltransferase(9), spectinomycin resistance); ΨTn554 (transposon: cadBC, cadmium salt resistance); Tn4001 (transposon: aacA-aphD, acetyltransferase/fosfotransferase AAC(6′)-Ie/APH(2”)-Ia, aminoglycoside resistance); SCCHg (chromosomal cassette: merRTAB, mercury salt resistance; IS431; Tn554; ccrC); hsdRSM—endonuclease (hsdR), methylase (hsdM) genes conditioning type I modification-restriction system; cadDX—cadmium salt resistance genes; arsDARBC, arsRBC—arsenate resistance genes; SCCBA01611 (24. 3 kb, ccrA1); SCCpls (12 kb); ACME II’(14 kb, arcCBDA gene cluster, IS256); SCCSC640 (14 kb; teichoic acid bisynthesis protein F gene; speG, spermidine N-acetyltransferase; ccrAB4, chromosomal recombinase; copA, copper transforming ATPase).
Table 4. CA-MRSA clones.
Table 4. CA-MRSA clones.
CCCloneSpa TypeAgr TypePVLOther Name of Clone
1ST1-IV/Vt125; t127; t128; t175; t273; t558; t1178; t1272; t1274 t1784; t53883+/-USA400; MW2; WA MRSA 1/45, 1/57; PFGE-1I; cMRSA; USA400 ORSA IV
1ST772-Vt345; t345; t657; t1839; t3387; t5414; t10795; 2+Bengal Bay Clone; WA MRSA 60
5ST5-IV/IV+ SCCfus/V/VIt001; t002; t003; t311; t450; t1277; t24602+Peadiatric; Maltese; USA800; HDE288; Portoguese peadiatric
8ST8-IVt008; t024; t064; t068; t112; t121; t451; t622; t14761+USA300; USA300-0114; USA300vLA; CMRSA10; PFGE-B; CA-MRSA/J
8ST72-IV/Vt126; t148; t324; t537; t6641+/-USA700 ORSA IV;
8ST2021-Vt024 +
9ST834-IVt1379; t9624 -
22ST22-IV/Vt005; t022; t032; t223; t310; t8911+/-UK EMRSA-15, Barnim; PFGE-B
30ST30-IVt019; t021; t318; t975; t12733+Oceania Southwest Pacific; Uruguayan 6; Mexican; USA1100; Southwest Pacific; PFGE-N; HKU-100
45ST45-IV/Vt004/t026/t0401 PFGE-E
59ST59-IV/V/VII t163; t172; t216; t316; t437; t528; t976; t35231+/-USA1000; HKU200; Western Australia MRSA-9, -15, -52, -55, -56, -73; Taiwan; Asian-Pacific, PFGE-A
59ST87-IVb (2B)t2161-Western Australia MRSA-24
59ST338-IV/Vt437; t4411+
80ST80-IVt044; t131; t359; t376; t639; t1199; t1200; t1201; t12063+/-European; PFGE-G2; cMRSA
88ST78-IVt186; t690; t786; t1598; t2832; t3205 -
88ST88-IVt168/t186/t690/t7293+/-African; PFGE-J
89ST89-IV -PFGE-1B
89ST91-IVt416/t604 PFGE-3B
93ST93-IVt2023+Queensland; PFGE-E
121ST121-Vt159/t314 +
152ST152-Vt355 +Balkan Region
152ST789-IVt547 +PFGE-1B
Abbreviations: CC, clonal compex MLST (multilocus sequence typing); ST, sequence types of MLST; Clone, sequence type of MLST -SCCmec type; Spa, S. aureus protein A; Agr, accessory gene regulator, quorum-sensing system, global regulatory system of S. aureus; PVL, Panton–Valentine leukocidin, +/- some variants +, and some -.
Table 5. HA-MRSA clones.
Table 5. HA-MRSA clones.
CCCloneSpa TypeAgr TypeOther Names
5ST5-I/IIt001; t002; t003; t214; t242; t311; t586; t24602UK EMRSA-3; Southern German MRSA, Rhine Hesse MRSA, Cordobes/ Chilean; PFGE-C; Geraldine; Pediatric; New York/Japan; USA100, CMRSA2; GISA
5ST225-IIt003; t014; t151, t1282; t1623 Rhine Hesse MRSA, EMRSA-3, New York
5ST228-It001; t0232Southern German MRSA, Rhine Hesse MRSA, EMRSA-3, New York
5ST764-IIt002; t1064
8ST8-II/IVt008; t064; t068; t1901Irish-1; UK EMRSA-2/-6/; USA500 ORSA IV, USA500 ORSA II, ST8 ORSA I, ST8 ORSA IV, ST8 ORSA III; Archaic/Iberian
8ST239-IIIt030; t0371Hungarian; Brazilian/Hungarian; UK EMRSA-1/-4/-11; Vienna; Australian, AUS-2, AUS-3 (2000); East Australian; PFGE-B; CC8/239; ST239 ORSA III; Eurasian; Brazilian; Portuguese; PFGE-B
8ST240-IIIt037 ST240 ORSA III,
8ST241-II/IIIt037; t1381Finland-UK
8ST247-It008; t051; t052; t0541Iberian, UK EMRSA-5/-7/-17; PFGE-A; ST247 ORSA I
8ST250-It008; t194; t2921/4Archaic, ST250 ORSA I; EMRSA-8
8ST254-I/IVt0091UK EMRSA-10, Hannover MRSA
22ST22-III/IV/Vt022; t032; t2231/2PFGE-B
30ST30-It018; t019; t037; t268; t3183EMRSA-16, USA200 ORSA II
30ST36-IIt018; t2683UK EMRSA-16; USA200; CMRSA4/8/9
45ST45-II/IVt004; t015; t026; t038; t4451/4USA600; CMRSA1; Berlin MRSA; USA600 ORSA II; USA600 ORSA IV
Abbreviations: as in the Table 4.
Table 6. LA-MRSA clones.
Table 6. LA-MRSA clones.
CCCloneSpa TypeAgr TypeOther Name
1ST1-IVat125; t127; t128; t11783USA400
5ST5-IVt002; t003; t3112PFGE-I
9ST9-III/IV/V/XII/IV+XIIt099; t100; t193; t411; t464, t526, t587, t800; t899; t1334, t1430; t2315; t2700; t3446; t4132; t4358; t4794; t13493; t299222GER-MRSA-ST9, CHN-MRSA-ST9
130ST130-XIt373, t843
398ST398-IV/V/VIIt011; t034; t571; t1197; t1250; t1255; t1451; t1456; t1928; t2510 1GER-MRSA-ST398, CHN-MRSA-ST398
398ST1232-V t034
Abbreviations: as in the Table 4.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Mlynarczyk-Bonikowska, B.; Kowalewski, C.; Krolak-Ulinska, A.; Marusza, W. Molecular Mechanisms of Drug Resistance in Staphylococcus aureus. Int. J. Mol. Sci. 2022, 23, 8088.

AMA Style

Mlynarczyk-Bonikowska B, Kowalewski C, Krolak-Ulinska A, Marusza W. Molecular Mechanisms of Drug Resistance in Staphylococcus aureus. International Journal of Molecular Sciences. 2022; 23(15):8088.

Chicago/Turabian Style

Mlynarczyk-Bonikowska, Beata, Cezary Kowalewski, Aneta Krolak-Ulinska, and Wojciech Marusza. 2022. "Molecular Mechanisms of Drug Resistance in Staphylococcus aureus" International Journal of Molecular Sciences 23, no. 15: 8088.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop