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Review

The Role of Bacterial Membrane Vesicles in the Dissemination of Antibiotic Resistance and as Promising Carriers for Therapeutic Agent Delivery

by
Md Jalal Uddin
1,†,
Jirapat Dawan
1,†,
Gibeom Jeon
1,
Tao Yu
2,
Xinlong He
3,* and
Juhee Ahn
1,*
1
Department of Medical Biomaterials Engineering, College of Biomedical Science, Kangwon National University, Chuncheon, Gangwon 24341, Korea
2
Shandong Institute of Parasitic Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences, Jining 272033, China
3
Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou 225001, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Microorganisms 2020, 8(5), 670; https://doi.org/10.3390/microorganisms8050670
Submission received: 29 March 2020 / Revised: 25 April 2020 / Accepted: 2 May 2020 / Published: 5 May 2020
(This article belongs to the Special Issue Control and Detection of Multiple Antibiotic Resistant Pathogens)
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Abstract

:
The rapid emergence and spread of antibiotic-resistant bacteria continues to be an issue difficult to deal with, especially in the clinical, animal husbandry, and food fields. The occurrence of multidrug-resistant bacteria renders treatment with antibiotics ineffective. Therefore, the development of new therapeutic methods is a worthwhile research endeavor in treating infections caused by antibiotic-resistant bacteria. Recently, bacterial membrane vesicles (BMVs) have been investigated as a possible approach to drug delivery and vaccine development. The BMVs are released by both pathogenic and non-pathogenic Gram-positive and Gram-negative bacteria, containing various components originating from the cytoplasm and the cell envelope. The BMVs are able to transform bacteria with genes that encode enzymes such as proteases, glycosidases, and peptidases, resulting in the enhanced antibiotic resistance in bacteria. The BMVs can increase the resistance of bacteria to antibiotics. However, the biogenesis and functions of BMVs are not fully understood in association with the bacterial pathogenesis. Therefore, this review aims to discuss BMV-associated antibiotic resistance and BMV-based therapeutic interventions.

1. Introduction

Over the last few decades, antibiotic resistance in bacteria has been a serious global threat to public health [1]. Antibiotic-resistant bacteria can survive current antibiotic regimens, resulting in frequent therapeutic failure [2]. The emergence of antibiotic-resistant bacteria spurred the necessity of developing new antibiotics [3,4]. The fundamental understanding of antibiotic resistance mechanisms is an important step in the development of effective therapeutic regimens. The intracellular levels of antibiotics are synergistically regulated by efflux pump systems and membrane permeability barriers [3]. Recently, it has been recognized that bacterial membrane vesicles (BMVs) may play a role in antibiotic resistance. Therefore, understanding the roles of BMVs can provide directions for the control of antibiotic-resistant pathogens.
The structural features of the bacterial outer membrane play an important role in the rapid adaptation to environmental stresses such as cold, heat, and antibiotic treatments, resulting in the evolution of antibiotic resistance in bacteria [2,5]. Therefore, the structure, biogenesis, function, and regulation of BMVs could be a new research area in connection with antibiotic resistance [6]. Although the biological functions of BMV-containing components have been considered important for understanding the mechanisms related to antibiotic resistance, there is still a lack of information on the biogenesis of BMVs in terms of antibiotic resistance [7]. Therefore, this review addresses the possible roles of BMVs in the control and prevention of the emergence of antibiotic-resistant bacteria.

2. Terminology and Characteristics of Bacterial Membrane Vesicles

The term BMV has been used to describe various extracellular substances, known as outer membrane vesicles (OMVs), which are specifically released from Gram-negative bacteria. Similarly, Gram-positive bacteria and archaea produce vesicles, known as membrane vesicles (MVs), and eukaryotic bacteria secrete surface and cellular lipids and proteins, named exosomes or microvesicles [8,9,10]. Therefore, the term OMV is not inclusive as there are many vesicle-producing Gram-positive bacteria. The BMV could be an inclusive term for membrane vesicles released from both Gram-negative (BMVGN) and Gram-positive (BMVGP) bacteria. The BMVs are nano-sized spherical membrane particles released from the bacterial membranes, encapsulating proteins, toxins, peptidoglycan, lipopolysaccharides (LPSs), and nucleic acids [11]. The BMVs have less than 370 kbp in DNA and are 10–300 nm in diameter [6,12]. The BMVs play an important role in bacterial cell-to-cell interactions [13]. The structural characteristics of BMVs (Figure 1) contribute to bacterial resistance to different types of environmental stresses [2,5].

3. Isolation and Purification of Bacterial Membrane Vesicles

Isolation, purification, and storage techniques have been developed to collect BMVs, which are essential steps for understanding structural and functional characteristics of BMVs [14]. Those techniques include conventional gradient centrifugation, column chromatography, immune affinity-based separation, and the proteomic approach [14,15,16]. The amount and content of BMVs varies depending on the bacterial growth conditions and genetic variation [17]. High purity is essential to characterize BMVs and applies for delivery system and vaccine development [18]. Differential centrifugation is used to remove non-BMVs in bacteria by serial centrifugation from 300 to 2000× g, and 10,000 to 100,000× g [19]. However, the differential centrifugation technique provides low yield and insufficient purity due to the repetitive ultracentrifugation [20]. Density gradient ultracentrifugation is applied to increase the separation efficiency of BMV particles according to the unique buoyant densities [21]. In addition, this method increases the yield of BMVs in terms of the purity of BMV fraction and the quantity of BMV proteins and RNAs. Hence, the density gradient ultracentrifugation method is considered one of the most suitable ways to purify BMVs [22]. However, the substantial loss of BMVs occurs in this method due to its complex, strenuous, and time consuming (>2 days) nature as well as its requirement for expensive equipment [23].
The filtration method is used to purify BMVs according to size. Many membrane filters with various pore sizes are useful for separating BMV particles. Ultrafiltration is a tangential flow filtration method with membrane pore sizes between 0.001 and 0.1 µm. The ultrafiltration can remove high molecular-weight substances such as viruses and organic and inorganic polymeric molecules [24]. However, this method is unable to efficiently purify the BMV fraction from non-BMV contents [25]. Gel filtration is known as size exclusion chromatography. This method can isolate molecules that have a different hydrodynamic radius and isolate proteins, polysaccharides, and BMVs. However, this method has a disadvantage, which is that it requires pre-processing, such as via ultracentrifuge or ultrafiltration [26,27]. Precipitation is usually used to purify proteins. Proteins are aggregated by adding a high concentration of salts, which can disturb the surface charges and hydrogen bonds to be easily isolated by centrifugation. This technique can also be used to isolate BMVs through dialysis [28].
A two-phase system with polyethylene glycol (PEG) and dextran is used to increase the purity of BMVs [29]. The BMVs and proteins are preferentially accumulated in the dextran phase and PEG phase, respectively. The repeated replacement of PEG can improve the purity of BMVs in the cell mixtures [30]. The surface components of BMVs, including proteins, lipids, and polysaccharides, are potential ligands binding to receptors. The specific binding affinity between ligands and receptors can be used to purify BMVs [31]. The affinity-based methods can improve the purity and selectivity of BMVs, but have disadvantages such as expensive antibodies, low isolation efficacy, and limited sample volume [32]. Thus, the affinity-based methods are further improved using a His-tag mutant and immobilized metal affinity chromatography (IMAC) [33]. The His-tag technology coupled with IMAC can selectively purify BMVs. The plasmid-encoded transmembrane proteins provide a His-tag sequence for bacterial outer membranes. Microfluidic devices based on microelectronic technology can adjust fluidic movement, and are able to handle viscous media in volumes ranging from picoliters to microliters. Microfluidic devices can reduce the sample quantity and processing time [31]. A microfluidic device with an immunoaffinity and membrane filter can rapidly and efficiently purify BMVs [34,35]. Since the purification methods for BMVs have advantages and disadvantages, an improved method still is needed to isolate BMVs with high purity.

4. Biogenesis of Bacterial Membrane Vesicles

The biogenesis (vesiculation) of BMVs is a physiological process, but its mechanisms still remain unknown [36]. BMVs might be produced through stochastic or regulated biogenesis mechanisms [37]. Current hypotheses on vesiculation propose that BMVs are forced out of the cell through the cell membrane and/or cell wall and contain the enzymes to destroy the peptidoglycan [10,38,39,40]. The vesiculation results from the outcome of the normal turnover of bacterial cells [41]. The BMVs are independently released from the bacterial cell envelope without alteration in membrane integrity [42]. The production of BMVs is an important step for bacteria to adapt to various stresses, including antibiotic treatment, heat, and acid [43]. The BMVs are constitutively produced in Gram-negative bacteria [5]. The factors which affect the BMV secretion in Gram-negative bacteria include various physiological and environmental stresses [44]. For instance, BMV production is triggered by antibiotics, high temperature, oxidizing agents, and nutrients [45]. In addition, two-component regulatory systems, such as PhoP/Q and PmrA/B, can modify LPS structure and regulate outer membrane proteins (OMPs) under acidic conditions [5]. Pseudomonas quinolone signals (PQSs), produced and secreted by the Pseudomonas species, can contribute to the generation of BMVs. The release of BMVs is attributed to the cell membrane charge and perturbation, including the interactions of LPS with divalent ions and membrane disruption stimulated by antibiotics, chelators, or hydrophobic compounds [8,46]. The BMV production is decreased in the presence of divalent ions (Mg2+) [8]. The production of BMVs from Staphylococcus aureus, Bacillus subtilis, and Streptococcus mutans occurs during coagulation and biofilm formation. The bacterial growth phases also contribute to the changes in the size and amount of BMVs; small, medium, and large BMVs are produced, respectively, in the early log phase, stationary phase, and mid-log phase [8,47]. Many researchers have made efforts to understand the regulation of BMV formation at the genetic level. The mutations in genes ypjA and nlpA, encoding cell envelope-localized proteins, can cause a decrease in the crosslinking level in peptidoglycan synthesis and promote the production of BMVs [48]. The overexpression of the genes associated with envelope stress response-related proteins can increase the production of BMVs without changes in membrane integrity [42]. Furthermore, the σE pathway could be activated in response to the misfolded OMP by upregulating several genes encoding periplasmic chaperones and proteases [49,50]. This could be due to specific σE- regulated proteins [50]. The BMV-associated RNAs can regulate the formation of vesicles. A previous study demonstrated that the small RNA in Vibrio cholerae, VrrA, can block the expression of OmpA, which stabilizes the outer membrane and peptidoglycan cross-links of the bacterial envelope and the suppression of OmpA, leading to the increase in vesiculation [51]. Moreover, the sRNAs, MicA, and RseX in Escherichia coli, and MicA and RybB in Salmonella have also been reported to downregulate the OmpA [52,53].
The BMV-producing bacteria induce an envelope stress response that provides the benefits of adaptation in the bacterial community [37]. The production of BMVs can be stimulated by envelope stress and other environmental conditions [42]. Moreover, the membrane-associated vesicular proteins, such as outer membrane proteins (OMPs) and transport proteins, act as functional barriers for various substances in accordance with hydrophobicity, electric charge, and polarity, leading to the development of antibiotic resistance in bacteria [54,55]. The decreased permeability of outer membranes results in the increased resistance to antibiotics such as colistin and polymyxin B [56]. Successively, the antibiotic-resistant bacteria are involved in the production of BMVs containing antibiotics [1]. In addition, antibiotics, including gentamicin, polymyxin, D-cycloserine, and mitomycin C, can induce the production of BMVs from Pseudomonas and Shigella [57,58]. A similar observation has also been reported for the production of BMVs in Escherichia coli O104:H4, and O157:H7 was increased in the presence of antibiotics such as ciprofloxacin, meropenem, fosfomycin, and polymyxin B [59]. The secreted BMVs help bacteria to survive antibiotic treatment by acting themselves as targets for antibiotics (Table 1) [60]. Interestingly, the BMVs bind peptide antibiotics with high affinity but do not bind well to hydrophobic antibiotics [1]. Mycobacterium BMVs contain various proteins, including virulence-associated proteins and toll-like receptor (TLR) ligands [61].

5. Biological Functions of Bacterial Membrane Vesicles

The BMVs play an important role in bacterial survival associated with intracellular communication under environmental stress conditions. The BMVs produced by Gram-negative bacteria contain lipids, proteins, LPSs, and genetic materials [13]. The vesiculation is influenced by the lipid A deacylase (PagL) [76]. The BMVs contain glycerophospholipids, phosphatidylglycerol, phosphatidylethanolamine, and cardiolipin in enterotoxigenic E. coli; phosphatidylglycerol and phosphatidylethanolamine in Pseudomonas syringae; and phosphatidylglycerols in Pseudomonas aeruginosa [77]. In addition, the enzymes that hydrolyze β-lactam antibiotics are packaged inside the BMVs of P. aeruginosa and then released by the cell [78]. The BMVs of Yersinia pestis contain a penicillin-binding protein activator that regulates peptidoglycan synthesis [79]. The BMVs produced by Gram-positive bacteria contain enzymes, toxins, hemolysin, and IgG-binding proteins. The BMVs have multifunctional properties that play a role in colonization, survival, antibiotic resistance, immunomodulation, autolysins, biofilm formation, virulence, and pathogenesis [41,80,81,82].
The BMVs in E. coli act as carriers to remove misfolded proteins from the bacterial cells [42]. The components of BMVs released from Gram-positive bacteria differ from those of BMVs released from Gram-negative bacteria that contain LPS and periplasmic components [38]. The misfolded proteins are accumulated in the periplasmic space and prevented by chaperones and proteases (DegP) [83]. The virulence factors, including β-lactamase, hemolysins, phospholipases, lipases, ureases, chitinases, proteases, molecular chaperones, and toxins, are found in BMVs [44,47,84]. For example, the BMVs in P. aeruginosa contain virulence factors such as proteases and hemolysin, which disrupt the quorum-sensing molecules and can lead to the lysis of Gram-negative and Gram-positive bacteria [84]. Previous studies have demonstrated that the BMVs contain various components, including periplasmic and cytoplasmic components, the inner membrane, and OMPs [6,43,47]. Therefore, the OMPs in BMVs, such as OmpA, OmpC, and OmpF, can act as virulence factors for evading the host immune response [13,55,85]. The BMVs provide many benefits for bacteria, including protection against enzymatic degradation, target specificity, sustainable toxin delivery, antibiotic resistance, immune evasion, bacterial invasion, and adherence [36,43,46,47]. The BMVs can protect bacteria from hydrophobic and peptide antibiotics that enhance membrane affinity [1,67]. Additionally, they help bacteria to increase their resistance to colistin and β-lactams, but do not cause any changes in the susceptibility to ciprofloxacin, streptomycin, and tetracycline [67]. The vesicles secreted from Gram-positive and Gram-negative bacteria can be possibly used for therapeutic development and antigen display [86].

6. Gene Transfer Potential of Bacterial Membrane Vesicles

The BMVs carry genetic materials and virulence factors, which are responsible for antibiotic resistance and pathogenesis. Pathogenic bacteria are more likely to secrete BMVs than nonpathogenic bacteria in order to survive under stressful conditions through biofilm formation and gene/nutrient transfer [15]. Various genetic materials have been identified from the BMVs produced by Gram-negative and Gram-positive bacteria (Table 2) [12,87,88]. Many studies have found the presence of DNA in BMVs that can be originated from chromosomes, plasmids, and bacteriophages [17,89]. Several types of RNAs, such as mRNA, rRNA, sRNA, and tRNA, have also been identified in BMVs [90]. Recent studies have reported that the BMVs produced by Neisseria gonorrhoeae, Prochlorococcus sp., and Porphyromonas gingivalis contain both DNAs and RNAs [91,92]. DNAs are supposed to be trapped into BMVs by several ways: by means of a cytoplasmic route, where the DNA from the cytoplasm is trapped with other components in inner and outer membrane vesicles; through a periplasmic route, where the DNA from the cytoplasmic site relocates to the periplasmic space, followed by arrest in BMVs; by an extracellular route, probably because of broken BMVs that re-annealed after liberation from the bacteria; or due to cell death [40,89,93,94]. In addition, bacteriophages can directly inject their DNA into BMVs [91]. RNAs together with the ribosomal proteins are encapsulated into BMVs through the routes described for DNA [92,95].
The BMVs can act as a vehicle for horizontal gene transfer into bacteria cells [105]. The gene transfer via BMVs is responsible for the microbial fitness determinants, including antimicrobial resistance, metabolic property, and virulence [1,89,102]. The antibiotic-sensitive E. coli can survive due to the BMV-containing β-lactamases responsible for the resistance to ampicillin, cefoperazone, and cefotaxime. Furthermore, the antibiotic resistance genes can be transferable to other bacteria through BMVs. For example, the BMV-producing E. coli contain transferable colistin and melittin resistance genes to P. aeruginosa and A. radioresistens, which lead to acquired resistance to membrane-disrupting antibiotics colistin and melittin [67]. Likewise, the BMVs from Acinetobacter baumannii are capable of transferring the OXA-24 carbapenemase gene, leading to the dissemination of antibiotic resistance in bacteria [89]. Additionally, the antibiotic resistance in E. coli is increased in the presence of BMVs. This assumes that the β-lactamases could be packaged into the vesicles during the biogenesis of BMVs due to their location in the periplasmic site of bacteria [106]. BMVs from Pseudomonas aeruginosa have been found to carry chromosomal β-lactamases, which can be transferred to other bacteria [72]. Furthermore, the cephalosporinase gene-containing BMVs secreted from Bacteroides spp. help gut pathogens exposed to β-lactam antibiotics survive [107]. Gram-positive bacteria, such as S. aureus, also produce BMVs containing the blaZ gene responsible for ampicillin resistance [108]. Multidrug resistant (MDR) bacteria acquire antibiotic resistance through many different mechanisms, including efflux pump activity, membrane permeability, biofilm formation, and enzymatic inactivation [106]. Bacterial porins and efflux pumps on the outer membrane play an important role in the development of multidrug resistance by selectively uptaking substrates and expelling intracellular antibiotics [41,105,109]. In addition, the BMVs involve interspecific and intraspecific transport of virulence genes. The BMV-producing bacteria contain multiple virulence factors, including proteases and leukotoxin from Actinobacillus actinomycetemcomitans, shiga toxin from E. coli, the vacA gene from Helicobacter pylori, and β-lactamase and alkaline phosphatase from P. aeruginosa [89]. Similarly, Bacillus anthracis produces BMVs containing toxins and anthrolysin, which can be transported to the host cells [110]. Therefore, BMVs could act as a vector in horizontal gene transfer that plays a vital role in the dissemination of antibiotic resistance among the bacteria. The BMVs can stimulate the formation of biofilm, and BMVs within biofilm can inactivate harmful molecules such as antibiotics, complements, and antibodies [13,111]. Quorum sensing (QS) is the strategy for surviving in a high density of bacteria, which produce quorum sensing molecules, known as auto-inducers, involved in adherence and biofilm formation. A previous study has reported that the hydrophobic QS molecules packed in BMVs are released from Vibrio harveyi during the stationary phase [112]. Moreover, the BMVs can facilitate the trafficking of QS signaling molecules produced by P. aeruginosa [41].

7. Proteomic Properties of Bacterial Membrane Vesicles

Proteins mostly contribute to the functional property of bacterial BMVs. Many researchers have extensively studied the identification of BMV-containing proteins using MS-based high-throughput proteomic analysis [113]. The conserved vesicular proteins can also provide valuable information for the biogenesis of BMVs in Gram-negative and Gram-positive bacteria [114]. The BMVs carry DNAs, and RNAs, and the translation of outer membrane proteins might coincide with their integration into the membrane, resulting in transcriptional and ribosomal proteins being integrated into BMVs [12,102]. The vesicular proteins OMPs, Tol-Pal, YbgF, and Lpps are involved in outer membrane integrity, which can contribute to the production of BMVs from the bacterial cell surface [115]. The peptidoglycan fragments are degraded by murein hydrolases, MltA, MipA, MltE, and SLP, and accumulated in the periplasmic site, resulting in the release of BMVs [116]. The cell wall-modifying enzymes in Gram-positive bacteria, including penicillin-binding proteins, lipoteichoic acid synthase, and N-acetylmuramoyl-l-alanine amidase, act as peptidoglycan hydrolase, leading to the vesicle formation [117]. The vesicular proteins are involved in a wide range of physiological and pathological functions, including host cell adhesion and invasion, antibiotic resistance, host cell destruction, immune system modulation, biofilm formation, and virulence promotion (Figure 2) [47].
The proteins secreted from BMVs have several distinct advantages over general secretory pathways, which are inaccessible to extracellular enzymes and transportable for a long distance [118]. For example, the vesicular proteins Ata, BabA, SabA, and OmpA, derived from H. pylori and A. baumannii, mediate adhesion to host cells [119,120]. The vesicular Ail protein can enhance the invasiveness of E. coli [121]. Furthermore, Staphopain A, a protein produced from S. aureus BMVs, plays an essential role in cellular invasion [122]. The BMVs produced by Gram-negative and Gram-positive bacteria can carry β-lactamases (AmpC and BlaZ), resulting in enhanced antibiotic resistance to β-lactam antibiotics [66,78]. The BMVs secreted from S. aureus are enriched in penicillin-binding proteins, which usually bind to β-lactam antibiotics and contribute to methicillin resistance [123]. The BMVs also harbor many multidrug efflux pump-related proteins (Mtr, Mex, and TolC) [1,124]. In addition, the BMVs carry several virulence factors, including toxins (α-hemolysis, cytolysin A, heat-labile enterotoxin, leukotoxin, shiga toxin, Cif, and β2 toxin), digestive enzymes (alkaline phosphatase, elastase, and haemolytic phospholipase C), and superantigens (SEQ, SSaA1, and SSaA2), which can play roles in damage to host cells and modulate the host immune responses [13,123,125,126,127,128,129]. The murein hydrolases (MltA and SLT), endopeptidase L5, peptidoglycan hydrolase, and amidase in BMVs are involved in killing competing bacteria by cell wall degradation [117,130,131]. The ATP-binding cassette (ABC) transporters for specific nutrients (BtuB, FhuA, and FadL) and hemin-binding protein C in BMVs have been reported to be nutrient sensors and carriers, responsible for the bacterial survival in nutrient deficiency [132,133]. The Porphyromonas gingivalis BMVs contain heme-binding lipoprotein (HmuY), which might be helpful in biofilm formation and cell survival during starvation periods [134]. The pathogen-associated lipoproteins from BMVs can promote inflammatory responses in the host [135]. Moreover, the BMVs secreted from Mycobacterium tuberculosis and Mycobacterium bovis contain lipoproteins, including LpqH, LppX, LprA, and PstS1, that act as virulence factors [136]. Taken together, the vesicular proteins can play significant roles in biogenesis and pathogenesis (Table 3).

8. Bacterial Membrane Vesicle-Based Therapeutic Approaches

The effectiveness of antibiotics in treating infectious diseases has been challenged due to the rapid spread of multidrug-resistant bacteria [163]. Therefore, alternative therapeutic methods are desperately needed in the clinical field. BMVs are nano-sized-vectors, responsible for the spread of virulence factors such as bacterial antigens, toxins, and antibiotic resistance-related genes [1]. Because of their structural and functional characteristics, the BMVs can be used to develop drug delivery platforms that prevent enzymatic degradation [164] and evade immune-mediated elimination [165]. The BMVs are promising candidates for developing antibiotic carriers and vaccines [14,86,165]. The BMVs contain pathogen-associated molecular patterns (PAMPs), which play an important role in innate immune stimulation and adaptive immune responses [43]. Bioengineered BMVs also have great benefits, including high specificity, loading efficacy, and stability [81]. Gentamicin-induced vesicles contain gentamicin, which can be used for the production of antibiotic carriers [153]. A recent study has observed that biocompatible BMVs encapsulate antibiotics and small interfering RNAs without adverse side effects [165]. In addition, BMVs can also encapsulate target antigens into the vesicle cavity or mosaic on the outer membrane through a certain mechanism, which is recognized by the host cell and causes an immune response, known as antigen presentation. BMVs also contain a variety of antigens, in addition to Toll-like receptor (TLR) agonists with natural adjuvant effects, including OMPs, lipoproteins, and LPSs. The advantages of BMVs include that they easily enter through the tissue cells and their surface molecules can be recognized by the immune system. Furthermore, the antigen-presenting dendritic cells can be stimulated by BMVs, leading to the induction of T and B cell-mediated immune protection [166]. Therefore, the application of BMVs has a very promising future as vaccine delivery vectors and in recombinant multivalent vaccines. For instance, E. coli BMVs can integrate and present heterologous OMPs and periplasmic proteins, and also can express Yersinia enterocolitica Ail protein with adhesion and invasion functions [121]. The modified BMVs of the Salmonella Typhimurium vaccine were used to present the Streptococcus pneumoniae model antigen, PspA, in the vesicle cavity, and provide immunization with nasal drops in mice [167]. The specific IgA antibody against PspA protects mice from lethal S. pneumoniae. Schroeder et al. [168] used proteins that penetrated the outer membrane, periplasmic space, non-adhesion bacterial surface protein, and KMP-11 antigen of the Leishmania parasite to fuse and express on Salmonella BMVs. Compared with the direct presentation of the KMP-11 antigen by attenuated Salmonella, its immune-boosting effect was increased by 40 times. A BMV delivery system was successfully established by fusion expression of heterologous antigens and OmpA genes, which provides a theoretical basis for BMVs as vaccine vectors [169]. Chen et al. [170] used E. coli BMVs to express a fusion protein and bacterial hemolysin CyA protein to induce an immune response against green fluorescent protein. Previous studies have shown that presenting heterologous antigens on the surface of BMVs can induce an effective immune response [171]. The BMVs containing immune-related molecules are a potential tool for vaccine development due to their immunogenicity and adjuvanticity [36,43,68,80,172]. The BMVs containing β-lactamase protein (BlaZ) are released from Gram-positive bacterium S. aureus. The development of an anti-β-lactamase antibody from BMVs can be used to increase the susceptibility of β-lactamase-producing bacteria to β-lactam antibiotics [1,173].
The BMVs released from pathogenic bacteria contain various cell surface components, such as capsular polysaccharides (CPSs) and LPSs, which can be specific targets for vaccine development [174]. Vaccines are considered to be the most direct and effective strategy to deal with bacterial diseases in the post-antibiotic era [175]. The membrane components contained in BMVs can stimulate the host to produce adaptive immune memory. The LPS contained in BMVs as an adjuvant can be used for a non-replicating vaccine. Since BMVs have achieved good results as a vaccine to prevent N. meningitidis infections, researchers have continued exploring the role of BMV vaccines against other pathogenic bacteria. The BMVs are naturally released by bacteria into the surrounding environment under normal growth conditions, which contain outer membrane antigens with natural conformation. Previous studies have shown that the components containing P. aeruginosa BMVs induced strong inflammatory responses [135]. The nasal immunization of mice with Hemophilus influenza BMVs not only induced strong mucosal and humoral immune responses, but also protected mice from heterologous influenza Haemophilus infections [176]. In addition, a mixture of Pasteurella multocida and Mannheimia haemolytica BMVs could induce strong specific mucosal and humoral immune responses [177]. These findings suggest that multiple BMV vaccines can be developed to protect against diseases caused by heterogeneous bacterial infections. Petersen et al. [178] immunized a cynomolgus monkey with Burkholderia pseudomallei BMVs, and the BMVs provided humoral immune protection against related proteins and LPSs.
BMVs contain many immunogens, including pathogenicity island-encoded proteins, OMPs, and chaperones. The composition of OMPs modulated by stresses and sRNA is responsible for the biogenesis of BMVs [179]. MicA induces OmpA and OmpC, which are involved in BMV production and immune response against bacteria [179]. The expression of OmpA, which is regulated by small RNAs, is negatively associated with the production of BMVs in Salmonella (RybB), Vibrio (VrrA), and E. coli (MicA) [37]. The various components of BMVs can be used to develop multivalent immunogenic vaccines [43,180]. For instance, the factor H-binding protein in N. meningitides plays an important role as a vaccine candidate. Additionally, the antigens and immune stimulators extracted from BMVs can be used for vaccine development. Previous studies have demonstrated that the Mycobacterium BMVs containing vesicle-associated antigens can be used for vaccine development to treat tuberculosis and potential biomarkers to selectively detect antibiotic-resistant bacteria [61,181]. Adjuvants are commonly used to combine with antigens to increase a weak immune response system [182]. Furthermore, the aluminum adjuvant was first practically applied for a human vaccine that was proven to be safe according to the vaccination schedules [183]. The benefits of using adjuvants include low cost, widespread circulation, and effective immune stimulation [184].
Adjuvants are substances that can assist vaccines by enhancing antigen-specific immune responses. The immune response induced by nasal immunity is not sufficient, so protein vaccines such as cholera toxin and E. coli heat labile enterotoxin may be used as adjuvants to increase the immune response [185]. However, the vaccine adjuvants have a disadvantage regarding safety. For example, nasal influenza vaccine mixed with E. coli heat-resistant toxins as a mucosal adjuvant may cause facial paralysis [186]. BMVs act as relatively safe adjuvants and can induce a highly effective immune response. N. meningitidis BMV vaccine has been used in many countries and can provide effective immune protection to adults or children [187]. Mixed inoculation of N. meningitidis BMVs with an influenza vaccine can significantly enhance the mucosal and systemic immune response [188]. In addition, several studies have found that mixed immunization of mice with BMVs and tumor-associated antigen gangliosides with low immunogenicity can stimulate the immune response to tumor antigens, enhancing the ability to resist cancer invasion [189]. Previous reports have proved that the immunopotent combination of virus-like particles (VLPs) and BMVs of N. meningitidis group B could induce anti-HIV-1 IgG and IgG2a, and also increase the production of IFN-gamma [184]. BMVs are also an effective mucosal adjuvant. Sardinas et al. [190] immunized mice by mixing OMVs of N. lactis with hepatitis B surface antigen HBsAg. Compared with the control group immunized with the hepatitis B surface antigen HBsAg alone, the mixed group induced high levels of HBsAg-specific IgA and IgG antibodies. Although a large number of tests have shown that BMVs can be a good vaccine choice, BMVs without any modification still have toxicity as a vaccine. For Gram-negative bacteria, BMV vaccination is limited by the incorporation of LPS or lipooligosaccharide (LOS) into the bilayer of BMVs. In order to use BMVs as a safe delivery vector, Kim et al. [169] mutated the MsbB gene encoding E. coli lipid A acyltransferase, which reduces the toxicity of LPS. BMVs derived from S. aureus could contain some species-specific virulence factors responsible for the safety of a potential vaccine [191]. However, Yuan et al. constructed an agr locus deletion mutant of the S. aureus strain (RN4220-Deltaagr) to reduce potential toxicity. Administration of such engineered (Deltaagr) BMVs in mice induced antibodies against all four dengue virus serotypes [192]. In addition, probiotic bacteria are known as generally recognized as safe (GRAS). BMVs from probiotic Nissle 1917 and gut resident E. coli strains distinctly modulate human dendritic cells and subsequent T cell responses [193]. Lactobacillus plantarum-derived BMVs can effectively protect atopic dermatitis induced by S. aureus-derived BMVs [194]. Therefore, the expression and further encapsulation of proteins into BMVs could represent a scientific novelty in BMV vaccination.

9. Conclusions

BMVs, derived from Gram-negative and Gram-positive bacteria, are considered to play a crucial role in intercellular communication between bacteria, and between bacteria and host. However, the mechanism of BMV biogenesis and its interaction with the host are still far from our understanding. Bacteria tend to produce more BMVs as a survival mechanism in response to unfavorable conditions such as antibiotic exposure. BMVs play an important role as carriers of antibiotic-related proteins and in inactivating antibiotic enzymes. Therefore, these vesicles are the major protective agents for bacterial growth and survival in the presence of antibiotics. In addition, purification and production are potentially important for BMVs to be used as vaccines. Vaccines have been widely applied to protect human health from infectious diseases. Recently, BMVs have gained attention as potential vaccine candidates due to their stability and protection against pathogens. BMVs have been applied as vaccines for inducing protective immune responses to human pathogens such as N. meningitides, Bordetella pertussis, and B. pseudomallei. One promising vaccine against pathogenic bacteria is the cell surface polysaccharide, coordinated with BMV formation. BMVs can be a promising platform for vaccine development. Therefore, BMVs have great potential for the design of a vaccine delivery platform to effectively control antibiotic-resistant pathogens.

Author Contributions

M.J.U. worked on the proteomic characteristics of BMVs, J.D. updated the BMV in association with antibiotic resistance mechanisms, G.J. contributed to the writing on the BMV isolation and purification, T.Y. was involved in collecting and updating BMV-producing bacteria, X.H. worked on the vaccine development using BMVs and updated the therapeutic aspect of BMVs, and J.A. drafted and revised the manuscript. All authors read and approved the final manuscript.

Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A3B01008304) and the Open Project Program of Jiangsu Key Laboratory of Zoonosis (R1908).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Chattopadhyay, M.K.; Jaganandham, M.V. Vesicles-mediated resistance to antibiotics in bacteria. Front. Microbiol. 2015, 6, 758. [Google Scholar] [CrossRef] [Green Version]
  2. Ghai, I.; Ghai, S. Understanding antibiotic resistance via outer membrane permeability. Infect. Drug Resist. 2018, 11, 523–530. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Zgurskaya, H.I.; Rybenkov, V.V.; Krishnamoorthy, G.; Leus, I.V. Trans-envelope multidrug efflux pumps of Gram-negative bacteria and their synergism with the outer membrane barrier. Res. Microbiol. 2018, 169, 351–356. [Google Scholar] [CrossRef] [PubMed]
  4. Podolsky, S.H. The evolving response to antibiotic resistance (1945–2018). Palgrave Commun. 2018, 4, 124. [Google Scholar] [CrossRef]
  5. Bonnington, K.E.; Kuehn, M.J. Outer membrane vesicle production facilitates LPS remodeling and outer membrane maintenance in Salmonella during environmental transitions. mBio 2016, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Bai, J.; Kim, S.I.; Ryu, S.; Yoon, H. Identification and characterization of outer membrane vesicle-associated proteins in Salmonella enterica serovar Typhimurium. Infect. Immun. 2014, 82, 4001–4010. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Beceiro, A.; Tomás, M.; Bou, G. Antimicrobial resistance and virulence: A successful or deleterious association in the bacterial world? Clin. Microbiol. Rev. 2013, 26, 185–230. [Google Scholar] [CrossRef] [Green Version]
  8. Deatherage, B.L.; Cookson, B.T. Membrane vesicle release in bacteria, eukaryotes, and archaea: A Conserved yet underappreciated aspect of microbial life. Infect. Immun. 2012, 80, 1948–1957. [Google Scholar] [CrossRef] [Green Version]
  9. Camussi, G.; Deregibus, M.C.; Bruno, S.; Cantaluppi, V.; Biancone, L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 2010, 78, 838–848. [Google Scholar] [CrossRef] [Green Version]
  10. Brown, L.; Wolf, J.M.; Prados-Rosales, R.; Casadevall, A. Through the wall: Extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi. Nat. Rev. Microbiol. 2015, 13, 620–630. [Google Scholar] [CrossRef] [Green Version]
  11. Yang, Y.; Hong, Y.; Cho, E.; Kim, G.B.; Kim, I.-S. Extracellular vesicles as a platform for membrane-associated therapeutic protein delivery. J. Extracell. Ves. 2018, 7, 1440131. [Google Scholar] [CrossRef] [Green Version]
  12. Dorward, D.W.; Garon, C.F.; Judd, R.C. Export and intercellular transfer of DNA via membrane blebs of Neisseria gonorrhoeae. J. Bacteriol. 1989, 171, 2499–2505. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Jan, A.T. Outer membrane vesicles (OMVs) of Gram-negative bacteria: A perspective update. Front. Microbiol. 2017, 8, 1053. [Google Scholar] [CrossRef] [PubMed]
  14. Jain, S.; Pillai, J. Bacterial membrane vesicles as novel nanosystems for drug delivery. Int. J. Nanomed. 2017, 12, 6329–6341. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Yun, S.H.; Park, E.C.; Lee, S.-Y.; Lee, H.; Choi, C.-W.; Yi, Y.-S.; Ro, H.-J.; Lee, J.C.; Jun, S.; Kim, H.-Y.; et al. Antibiotic treatment modulates protein components of cytotoxic outer membrane vesicles of multidrug-resistant clinical strain, Acinetobacter baumannii DU202. Clin. Proteom. 2018, 15, 28. [Google Scholar] [CrossRef]
  16. Dauros Singorenko, P.; Chang, V.; Whitcombe, A.; Simonov, D.; Hong, J.; Phillips, A.; Swift, S.; Blenkiron, C. Isolation of membrane vesicles from prokaryotes: A technical and biological comparison reveals heterogeneity. J. Extracell. Ves. 2017, 6, 1324731. [Google Scholar] [CrossRef]
  17. Orench-Rivera, N.; Kuehn, M.J. Environmentally controlled bacterial vesicle-mediated export. Cell. Microbiol. 2016, 18, 1525–1536. [Google Scholar] [CrossRef] [Green Version]
  18. Chutkan, H.; MacDonald, I.; Manning, A.; Kuehn, M.J. Quantitative and qualitative preparations of bacterial outer membrane vesicles. In Bacterial Cell Surfaces; Springer: Berlin/Heidelberg, Germany, 2013; pp. 259–272. [Google Scholar]
  19. Nühse, T.S.; Stensballe, A.; Jensen, O.N.; Peck, S.C. Large-scale analysis of in vivo phosphorylated membrane proteins by immobilized metal ion affinity chromatography and mass spectrometry. Mol. Cell. Proteom. 2003, 2, 1234–1243. [Google Scholar] [CrossRef] [Green Version]
  20. Livshits, M.A.; Khomyakova, E.; Evtushenko, E.G.; Lazarev, V.N.; Kulemin, N.A.; Semina, S.E.; Generozov, E.V.; Govorun, V.M. Isolation of exosomes by differential centrifugation: Theoretical analysis of a commonly used protocol. Sci. Rep. 2015, 5, 17319. [Google Scholar] [CrossRef]
  21. Fernández-Llama, P.; Khositseth, S.; Gonzales, P.A.; Star, R.A.; Pisitkun, T.; Knepper, M.A. Tamm-Horsfall protein and urinary exosome isolation. Kidney Int. 2010, 77, 736–742. [Google Scholar] [CrossRef] [Green Version]
  22. Abramowicz, A.; Widlak, P.; Pietrowska, M. Proteomic analysis of exosomal cargo: The challenge of high purity vesicle isolation. Mol. Biosyst. 2016, 12, 1407–1419. [Google Scholar] [CrossRef] [PubMed]
  23. Lobb, R.J.; Becker, M.; Wen Wen, S.; Wong, C.S.; Wiegmans, A.P.; Leimgruber, A.; Möller, A. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J. Extracell. Ves. 2015, 4, 27031. [Google Scholar] [CrossRef] [PubMed]
  24. Spatz, D.D.; Friedlander, R. Ultrafiltration—The membranes, the process and its application to organic molecule fractionation. In Ultrafiltration Membranes and Applications; Springer: Berlin/Heidelberg, Germany, 1980; p. 603. [Google Scholar]
  25. Junker, K.; Heinzelmann, J.; Beckham, C.; Ochiya, T.; Jenster, G. Extracellular vesicles and their role in urologic malignancies. Eur. Urol. 2016, 70, 323–331. [Google Scholar] [CrossRef] [PubMed]
  26. Salih, M.; Zietse, R.; Hoorn, E.J. Urinary extracellular vesicles and the kidney: Biomarkers and beyond. Am. J. Physiol.-Ren. Physiol. 2014, 306, F1251–F1259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Nordin, J.Z.; Lee, Y.; Vader, P.; Mäger, I.; Johansson, H.J.; Heusermann, W.; Wiklander, O.P.; Hällbrink, M.; Seow, Y.; Bultema, J.J. Ultrafiltration with size-exclusion liquid chromatography for high yield isolation of extracellular vesicles preserving intact biophysical and functional properties. Nanomed. Nanotechnol. Biol. Med. 2015, 11, 879–883. [Google Scholar] [CrossRef] [Green Version]
  28. Klimentová, J.; Stulík, J. Methods of isolation and purification of outer membrane vesicles from gram-negative bacteria. Microbiol. Res. 2015, 170, 1–9. [Google Scholar] [CrossRef] [PubMed]
  29. Kim, J.; Shin, H.; Kim, J.; Kim, J.; Park, J. Isolation of high-purity extracellular vesicles by extracting proteins using aqueous two-phase system. PLoS ONE 2015, 10, e0129760. [Google Scholar] [CrossRef] [Green Version]
  30. Shin, H.; Han, C.; Labuz, J.M.; Kim, J.; Kim, J.; Cho, S.; Gho, Y.S.; Takayama, S.; Park, J. High-yield isolation of extracellular vesicles using aqueous two-phase system. Sci. Rep. 2015, 5, 13103. [Google Scholar] [CrossRef] [Green Version]
  31. Konoshenko, M.Y.; Lekchnov, E.A.; Vlassov, A.V.; Laktionov, P.P. Isolation of extracellular vesicles: General methodologies and latest trends. Biomed Res. Int. 2018, 2018, 8545347. [Google Scholar] [CrossRef]
  32. Ingato, D.; Lee, J.U.; Sim, S.J.; Kwon, Y.J. Good things come in small packages: Overcoming challenges to harness extracellular vesicles for therapeutic delivery. J. Control. Release 2016, 241, 174–185. [Google Scholar] [CrossRef] [Green Version]
  33. Alves, N.J.; Turner, K.B.; DiVito, K.A.; Daniele, M.A.; Walper, S.A. Affinity purification of bacterial outer membrane vesicles (OMVs) utilizing a His-tag mutant. Res. Microbiol. 2017, 168, 139–146. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. He, M.; Zeng, Y. Microfluidic exosome analysis toward liquid biopsy for cancer. J. Lab. Autom. 2016, 21, 599–608. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Guo, S.-C.; Tao, S.-C.; Dawn, H. Microfluidics-based on-a-chip systems for isolating and analysing extracellular vesicles. J. Extracell. Ves. 2018, 7, 1508271. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Gill, S.; Catchpole, R.; Forterre, P. Extracellular membrane vesicles in the three domains of life and beyond. Fems Microbiol. Rev. 2018, 43, 273–303. [Google Scholar] [CrossRef] [PubMed]
  37. Schwechheimer, C.; Sullivan, C.J.; Kuehn, M.J. Envelope control of outer membrane vesicle production in Gram-negative bacteria. Biochemistry 2013, 52, 3031–3040. [Google Scholar] [CrossRef] [PubMed]
  38. Liu, Y.; Defourny, K.A.Y.; Smid, E.J.; Abee, T. Gram-positive bacterial extracellular vesicles and their impact on health and disease. Front. Microbiol. 2018, 9, 1502. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Haurat, M.F.; Elhenawy, W.; Feldman Mario, F. Prokaryotic membrane vesicles: New insights on biogenesis and biological roles. Biol. Chem. 2015, 396, 95. [Google Scholar] [CrossRef]
  40. Berleman, J.; Auer, M. The role of bacterial outer membrane vesicles for intra- and interspecies delivery. Environ. Microbiol. 2013, 15, 347–354. [Google Scholar] [CrossRef]
  41. Jagannadham, M.V.; Chattopadhyay, M.K. Role of outer membrane vesicles of bacteria. Resonance 2015, 20, 711–725. [Google Scholar] [CrossRef]
  42. McBroom, A.J.; Kuehn, M.J. Release of outer membrane vesicles by Gram-negative bacteria is a novel envelope stress response. Mol. Microbiol. 2007, 63, 545–558. [Google Scholar] [CrossRef]
  43. Bartolini, E.; Ianni, E.; Frigimelica, E.; Petracca, R.; Galli, G.; Scorza, F.B.; Norais, N.; Laera, D.; Giusti, F.; Pierleoni, A.; et al. Recombinant outer membrane vesicles carrying Chlamydia muridarum HtrA induce antibodies that neutralize chlamydial infection in vitro. J. Extracell. Ves. 2013, 2, 20181. [Google Scholar] [CrossRef]
  44. Lagos, L.; Tandberg, J.I.; Repnik, U.; Boysen, P.; Ropstad, E.; Varkey, D.; Paulsen, I.T.; Winther-Larsen, H.C. Characterization and vaccine potential of membrane vesicles produced by Francisella noatunensis subsp. orientalis in an adult zebrafish model. Clin. Vaccine Immunol. 2017, 24, e00557-16. [Google Scholar]
  45. Kulp, A.; Kuehn, M.J. Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Ann. Rev. Microbiol. 2010, 64, 163–184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Horspool, A.M.; Schertzer, J.W. Reciprocal cross-species induction of outer membrane vesicle biogenesis via secreted factors. Sci. Rep. 2018, 8, 9873. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Bonnington, K.E.; Kuehn, M.J. Protein selection and export via outer membrane vesicles. Biochim. Biophys. Acta 2014, 1843, 1612–1619. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. McBroom, A.J.; Johnson, A.P.; Vemulapalli, S.; Kuehn, M.J. Outer membrane vesicle production by Escherichia coli is independent of membrane instability. J. Bacteriol. 2006, 188, 5385–5392. [Google Scholar] [CrossRef] [Green Version]
  49. Raivio, T.L. Envelope stress responses and Gram-negative bacterial pathogenesis. Mol. Microbiol. 2005, 56, 1119–1128. [Google Scholar] [CrossRef]
  50. Rhodius, V.A.; Suh, W.C.; Nonaka, G.; West, J.; Gross, C.A. Conserved and variable functions of the sigmaE stress response in related genomes. PLoS Biol. 2006, 4, e2. [Google Scholar] [CrossRef] [Green Version]
  51. Song, T.; Mika, F.; Lindmark, B.; Liu, Z.; Schild, S.; Bishop, A.; Zhu, J.; Camilli, A.; Johansson, J.; Vogel, J.; et al. A new Vibrio cholerae sRNA modulates colonization and affects release of outer membrane vesicles. Mol. Microbiol. 2008, 70, 100–111. [Google Scholar] [CrossRef] [Green Version]
  52. Udekwu, K.I.; Darfeuille, F.; Vogel, J.; Reimegård, J.; Holmqvist, E.; Wagner, E.G.H. Hfq-dependent regulation of OmpA synthesis is mediated by an antisense RNA. Genes Dev. 2005, 19, 2355–2366. [Google Scholar] [CrossRef] [Green Version]
  53. Papenfort, K.; Pfeiffer, V.; Mika, F.; Lucchini, S.; Hinton, J.C.D.; Vogel, J. SigmaE-dependent small RNAs of Salmonella respond to membrane stress by accelerating global omp mRNA decay. Mol. Microbiol. 2006, 62, 1674–1688. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Yun, S.-H.; Choi, C.-W.; Kwon, S.-O.; Park, G.W.; Cho, K.; Kwon, K.-H.; Kim, J.Y.; Yoo, J.S.; Lee, J.C.; Choi, J.-S.; et al. Quantitative proteomic analysis of cell wall and plasma membrane fractions from multidrug-resistant Acinetobacter baumannii. J. Proteome Res. 2011, 10, 459–469. [Google Scholar] [CrossRef] [PubMed]
  55. Ghai, I.; Ghai, S. Exploring bacterial outer membrane barrier to combat bad bugs. Infect. Drug Resist. 2017, 10, 261–273. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Trimble, M.J.; Mlynárčik, P.; Kolář, M.; Hancock, R.E.W. Polymyxin: Alternative mechanisms of action and resistance. Cold Spring Harb. Perspect. Med. 2016, 6, a025288. [Google Scholar] [CrossRef] [Green Version]
  57. Dutta, S.; Iida, K.-i.; Takade, A.; Meno, Y.; Nair, G.B.; Yoshida, S.-I. Release of shiga toxin by membrane vesicles in Shigella dysenteriae serotype 1 strains and in vitro effects of antimicrobials on toxin production and release. Microbiol. Immunol. 2004, 48, 965–969. [Google Scholar] [CrossRef] [Green Version]
  58. MacDonald, I.A.; Kuehn, M.J. Stress-induced outer membrane vesicle production by Pseudomonas aeruginosa. J. Bacteriol. 2013, 195, 2971–2981. [Google Scholar] [CrossRef] [Green Version]
  59. Bauwens, A.; Kunsmann, L.; Karch, H.; Mellmann, A.; Bielaszewska, M. Antibiotic-mediated modulations of outer membrane vesicles in Enterohemorrhagic Escherichia coli O104:H4 and O157:H7. Antimicrob. Agents Chemother. 2017, 61, e00937. [Google Scholar] [CrossRef] [Green Version]
  60. Sabnis, A.; Ledger, E.V.K.; Pader, V.; Edwards, A.M. Antibiotic interceptors: Creating safe spaces for bacteria. PLoS Path. 2018, 14, e1006924. [Google Scholar] [CrossRef]
  61. Lee, J.; Kim, S.-H.; Choi, D.-S.; Lee, J.S.; Kim, D.-K.; Go, G.; Park, S.-M.; Kim, S.H.; Shin, J.H.; Chang, C.L.; et al. Proteomic analysis of extracellular vesicles derived from Mycobacterium tuberculosis. Proteomics 2015, 15, 3331–3337. [Google Scholar] [CrossRef]
  62. Pader, V.; Hakim, S.; Painter, K.L.; Wigneshweraraj, S.; Clarke, T.B.; Edwards, A.M. Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids. Nat. Microbiol. 2016, 2, 16194. [Google Scholar] [CrossRef] [Green Version]
  63. Ledger, E.V.K.; Pader, V.; Edwards, A.M. Enterococcus faecalis and pathogenic streptococci inactivate daptomycin by releasing phospholipids. Microbiology 2017, 163, 1502–1508. [Google Scholar] [CrossRef]
  64. Manning, A.J.; Kuehn, M.J. Contribution of bacterial outer membrane vesicles to innate bacterial defense. BMC Microbiol. 2011, 11, 258. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Marsh, D. Thermodynamics of phospholipid self-assembly. Biophys. J. 2012, 102, 1079–1087. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Schaar, V.; Nordström, T.; Mörgelin, M.; Riesbeck, K. Moraxella catarrhalis outer membrane vesicles carry β-lactamase and promote survival of Streptococcus pneumoniae and Haemophilus influenzae by inactivating amoxicillin. Antimicrob. Agents Chemother. 2011, 55, 3845–3853. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Kulkarni, H.M.; Nagaraj, R.; Jagannadham, M.V. Protective role of E. coli outer membrane vesicles against antibiotics. Microbiol. Res. 2015, 181, 1–7. [Google Scholar] [CrossRef]
  68. Schwechheimer, C.; Kuehn, M.J. Outer-membrane vesicles from Gram-negative bacteria: Biogenesis and functions. Nat. Rev. Microbiol. 2015, 13, 605–619. [Google Scholar] [CrossRef] [Green Version]
  69. Campos, M.A.; Vargas, M.A.; Regueiro, V.; Llompart, C.M.; Albertí, S.; Bengoechea, J.A. Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides. Infect. Immun. 2004, 72, 7107–7114. [Google Scholar] [CrossRef] [Green Version]
  70. Jones, A.; Geörg, M.; Maudsdotter, L.; Jonsson, A.-B. Endotoxin, capsule, and bacterial attachment contribute to Neisseria meningitidis resistance to the human antimicrobial peptide LL-37. J. Bacteriol. 2009, 191, 3861–3868. [Google Scholar] [CrossRef] [Green Version]
  71. Llobet, E.; Tomás, J.M.; Bengoechea, J.A. Capsule polysaccharide is a bacterial decoy for antimicrobial peptides. Microbiology 2008, 154, 3877–3886. [Google Scholar] [CrossRef] [Green Version]
  72. Geisinger, E.; Isberg, R.R. Antibiotic modulation of capsular exopolysaccharide and virulence in Acinetobacter baumannii. PLoS Path. 2015, 11, e1004691. [Google Scholar] [CrossRef] [Green Version]
  73. Billings, N.; Ramirez Millan, M.; Caldara, M.; Rusconi, R.; Tarasova, Y.; Stocker, R.; Ribbeck, K. The extracellular matrix component psl provides fast-acting antibiotic defense in Pseudomonas aeruginosa biofilms. PLoS Path. 2013, 9, e1003526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Chiang, W.-C.; Nilsson, M.; Jensen, P.Ø.; Høiby, N.; Nielsen, T.E.; Givskov, M.; Tolker-Nielsen, T. Extracellular DNA shields against aminoglycosides in Pseudomonas aeruginosa biofilms. Antimicrob. Agents Chemother. 2013, 57, 2352–2361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Doroshenko, N.; Tseng, B.S.; Howlin, R.P.; Deacon, J.; Wharton, J.A.; Thurner, P.J.; Gilmore, B.F.; Parsek, M.R.; Stoodley, P. Extracellular DNA impedes the transport of vancomycin in Staphylococcus epidermidis biofilms preexposed to subinhibitory concentrations of vancomycin. Antimicrob. Agents Chemother. 2014, 58, 7273–7282. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Elhenawy, W.; Bording-Jorgensen, M.; Valguarnera, E.; Haurat, M.F.; Wine, E.; Feldman, M.F. LPS remodeling triggers formation of outer membrane vesicles in Salmonella. mBio 2016, 7, e00940-16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Tashiro, Y.; Inagaki, A.; Shimizu, M.; Ichikawa, S.; Takaya, N.; Nakajima-Kambe, T.; Uchiyama, H.; Nomura, N. Characterization of phospholipids in membrane vesicles derived from Pseudomonas aeruginosa. Biosci. Biotechnol. Biochem. 2011, 75, 605–607. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Ciofu, O.; Beveridge, T.J.; Kadurugamuwa, J.; Walther-Rasmussen, J.; Høiby, N. Chromosomal β-lactamase is packaged into membrane vesicles and secreted from Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2000, 45, 9–13. [Google Scholar] [CrossRef]
  79. Eddy, J.L.; Gielda, L.M.; Caulfield, A.J.; Rangel, S.M.; Lathem, W.W. Production of outer membrane vesicles by the plague pathogen Yersinia pestis. PLoS ONE 2014, 9, e107002. [Google Scholar] [CrossRef]
  80. Chan, K.W.; Shone, C.; Hesp, J.R. Antibiotics and iron-limiting conditions and their effect on the production and composition of outer membrane vesicles secreted from clinical isolates of extraintestinal pathogenic E. coli. Proteomics 2017, 11, 1600091. [Google Scholar] [CrossRef]
  81. Wang, S.; Gao, J.; Wang, Z. Outer membrane vesicles for vaccination and targeted drug delivery. Nanomed Nanobiotechnol 2018, 11, e1523. [Google Scholar] [CrossRef]
  82. Baker, S.; Davitt, C.; Morici, L. Gram-negative bacterial outer membrane vesicles inhibit growth of multidrug-resistant organisms and induce wound-healing cytokines. Open Forum Infect. Dis. 2016, 3, 2242. [Google Scholar] [CrossRef]
  83. Pan, K.-L.; Hsiao, H.-C.; Weng, C.-L.; Wu, M.-S.; Chou, C.P. Roles of DegP in prevention of protein misfolding in the periplasm upon overexpression of penicillin acylase in Escherichia coli. J. Bacteriol. 2003, 185, 3020–3030. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Tashiro, Y.; Toyofuku, M.; Nakajima-Kambe, T.; Uchiyama, H.; Nomura, N. Bicyclic compounds repress membrane vesicle production and Pseudomonas quinolone signal synthesis in Pseudomonas aeruginosa. FEMS Microbiol. Lett. 2010, 304, 123–130. [Google Scholar] [CrossRef] [PubMed]
  85. Rollauer, S.E.; Sooreshjani, M.A.; Noinaj, N.; Buchanan, S.K. Outer membrane protein biogenesis in Gram-negative bacteria. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2015, 370, 20150023. [Google Scholar] [CrossRef] [PubMed]
  86. Bitto, N.; Kaparakis-Liaskos, M. The therapeutic benefit of bacterial membrane vesicles. Int. J. Mol. Sci. 2017, 18, 1287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Klieve, A.V.; Yokoyama, M.T.; Forster, R.J.; Ouwerkerk, D.; Bain, P.A.; Mawhinney, E.L. Naturally occurring DNA transfer system associated with membrane vesicles in cellulolytic Ruminococcus spp. of ruminal origin. Appl. Environ. Microbiol. 2005, 71, 4248–4253. [Google Scholar] [CrossRef] [Green Version]
  88. Chiura, H.X.; Kogure, K.; Hagemann, S.; Ellinger, A.; Velimirov, B. Evidence for particle-induced horizontal gene transfer and serial transduction between bacteria. FEMS Microbiol. Ecol. 2011, 76, 576–591. [Google Scholar] [CrossRef] [Green Version]
  89. Rumbo, C.; Fernández-Moreira, E.; Merino, M.; Poza, M.; Mendez, J.A.; Soares, N.C.; Mosquera, A.; Chaves, F.; Bou, G. Horizontal transfer of the OXA-24 carbapenemase gene via outer membrane vesicles: A new mechanism of dissemination of carbapenem resistance genes in Acinetobacter baumannii. Antimicrob. Agents Chemother. 2011, 55, 3084–3090. [Google Scholar] [CrossRef] [Green Version]
  90. Domingues, S.; Nielsen, K.M. Membrane vesicles and horizontal gene transfer in prokaryotes. Curr. Opin. Microbiol. 2017, 38, 16–21. [Google Scholar] [CrossRef]
  91. Biller, S.J.; Schubotz, F.; Roggensack, S.E.; Thompson, A.W.; Summons, R.E.; Chisholm, S.W. Bacterial vesicles in marine ecosystems. Science 2014, 343, 183–186. [Google Scholar] [CrossRef]
  92. Sjöström, A.E.; Sandblad, L.; Uhlin, B.E.; Wai, S.N. Membrane vesicle-mediated release of bacterial RNA. Sci. Rep. 2015, 5, 15329. [Google Scholar] [CrossRef] [Green Version]
  93. Renelli, M.; Matias, V.; Lo, R.Y.; Beveridge, T.J. DNA-containing membrane vesicles of Pseudomonas aeruginosa PAO1 and their genetic transformation potential. Microbiology 2004, 150, 2161–2169. [Google Scholar] [CrossRef] [PubMed]
  94. Fulsundar, S.; Harms, K.; Flaten, G.E.; Johnsen, P.J.; Chopade, B.A.; Nielsen, K.M. Gene transfer potential of outer membrane vesicles of Acinetobacter baylyi and effects of stress on vesiculation. Appl. Environ. Microbiol. 2014, 80, 3469–3483. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Blenkiron, C.; Simonov, D.; Muthukaruppan, A.; Tsai, P.; Dauros, P.; Green, S.; Hong, J.; Print, C.G.; Swift, S.; Phillips, A.R. Uropathogenic Escherichia coli releases extracellular vesicles that are associated with RNA. PLoS ONE 2016, 11, e0160440. [Google Scholar] [CrossRef] [PubMed]
  96. Jiang, Y.; Kong, Q.; Roland, K.L.; Curtiss, R., 3rd. Membrane vesicles of Clostridium perfringens type A strains induce innate and adaptive immunity. Int. J. Med. Microbiol. 2014, 304, 431–443. [Google Scholar] [CrossRef] [Green Version]
  97. Ho, M.-H.; Chen, C.-H.; Goodwin, J.S.; Wang, B.-Y.; Xie, H. Functional advantages of Porphyromonas gingivalis vesicles. PLoS ONE 2015, 10, e0123448. [Google Scholar] [CrossRef]
  98. Blesa, A.; Berenguer, J. Contribution of vesicle-protected extracellular DNA to horizontal gene transfer in Thermus spp. Int. Microbiol. 2015, 18, 177–187. [Google Scholar]
  99. Pérez-Cruz, C.; Carrión, O.; Delgado, L.; Martinez, G.; López-Iglesias, C.; Mercade, E. New type of outer membrane vesicle produced by the Gram-negative bacterium Shewanella vesiculosa M7T: Implications for DNA content. Appl. Environ. Microbiol. 2013, 79, 1874–1881. [Google Scholar] [CrossRef] [Green Version]
  100. Rath, P.; Huang, C.; Wang, T.; Wang, T.; Li, H.; Prados-Rosales, R.; Elemento, O.; Casadevall, A.; Nathan, C.F. Genetic regulation of vesiculogenesis and immunomodulation in Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 2013, 110, E4790–E4797. [Google Scholar] [CrossRef] [Green Version]
  101. Liao, S.; Klein, M.I.; Heim, K.P.; Fan, Y.; Bitoun, J.P.; Ahn, S.-J.; Burne, R.A.; Koo, H.; Brady, L.J.; Wen, Z.T. Streptococcus mutans extracellular DNA is upregulated during growth in biofilms, actively released via membrane vesicles, and influenced by components of the protein secretion machinery. J. Bacteriol. 2014, 196, 2355–2366. [Google Scholar] [CrossRef] [Green Version]
  102. Yaron, S.; Kolling, G.L.; Simon, L.; Matthews, K.R. Vesicle-mediated transfer of virulence genes from Escherichia coli O157:H7 to other enteric bacteria. Appl. Environ. Microbiol. 2000, 66, 4414–4420. [Google Scholar] [CrossRef] [Green Version]
  103. Medvedeva, E.S.; Baranova, N.B.; Mouzykantov, A.A.; Grigorieva, T.Y.; Davydova, M.N.; Trushin, M.V.; Chernova, O.A.; Chernov, V.M. Adaptation of Mycoplasmas to antimicrobial agents: Acholeplasma laidlawii extracellular vesicles mediate the export of ciprofloxacin and a mutant gene related to the antibiotic target. Sci. World J. 2014, 2014, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Lee, J.H.; Choi, C.-W.; Lee, T.; Kim, S.I.; Lee, J.-C.; Shin, J.-H. Transcription factor σB plays an important role in the production of extracellular membrane-derived vesicles in Listeria monocytogenes. PLoS ONE 2013, 8, e73196. [Google Scholar] [CrossRef] [PubMed]
  105. Kim, S.W.; Park, S.B.; Im, S.P.; Lee, J.S.; Jung, J.W.; Gong, T.W.; Lazarte, J.M.S.; Kim, J.; Seo, J.-S.; Kim, J.-H.; et al. Outer membrane vesicles from β-lactam-resistant Escherichia coli enable the survival of β-lactam-susceptible E. coli in the presence of β-lactam antibiotics. Sci. Rep. 2018, 8, 5402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Devos, S.; Stremersch, S.; Raemdonck, K.; Braeckmans, K.; Devreese, B. Intra- and Interspecies effects of outer membrane vesicles from Stenotrophomonas maltophilia on β-lactam resistance. Antimicrob. Agents Chemother. 2016, 60, 2516–2518. [Google Scholar] [CrossRef] [Green Version]
  107. Stentz, R.; Horn, N.; Cross, K.; Salt, L.; Brearley, C.; Livermore, D.M.; Carding, S.R. Cephalosporinases associated with outer membrane vesicles released by Bacteroides spp. protect gut pathogens and commensals against β-lactam antibiotics. J. Antimicrob. Chemother. 2015, 70, 701–709. [Google Scholar] [CrossRef] [Green Version]
  108. Lee, J.; Lee, E.-Y.; Kim, S.-H.; Kim, D.-K.; Park, K.-S.; Kim, K.P.; Kim, Y.-K.; Roh, T.-Y.; Gho, Y.S. Staphylococcus aureus extracellular vesicles carry biologically active β-lactamase. Antimicrob. Agents Chemother. 2013, 57, 2589–2595. [Google Scholar] [CrossRef] [Green Version]
  109. Webber, M.A.; Piddock, L.J.V. The importance of efflux pumps in bacterial antibiotic resistance. J. Antimicrob. Chemother. 2003, 51, 9–11. [Google Scholar] [CrossRef]
  110. Rivera, J.; Cordero, R.J.B.; Nakouzi, A.S.; Frases, S.; Nicola, A.; Casadevall, A. Bacillus anthracis produces membrane-derived vesicles containing biologically active toxins. Proc. Natl. Acad. Sci. USA 2010, 107, 19002–19007. [Google Scholar] [CrossRef] [Green Version]
  111. Kulkarni, H.M.; Swamy, C.V.B.; Jagannadham, M.V. Molecular characterization and functional analysis of outer membrane vesicles from the antarctic bacterium Pseudomonas syringae suggest a possible response to environmental conditions. J. Proteome Res. 2014, 13, 1345–1358. [Google Scholar] [CrossRef]
  112. Brameyer, S.; Plener, L.; Müller, A.; Klingl, A.; Wanner, G.; Jung, K. Outer membrane vesicles facilitate trafficking of the hydrophobic signaling molecule CAI-1 between Vibrio harveyi cells. J. Bacteriol. 2018, 200, e00740. [Google Scholar] [CrossRef] [Green Version]
  113. Kim, D.-K.; Kang, B.; Kim, O.Y.; Choi, D.-S.; Lee, J.; Kim, S.R.; Go, G.; Yoon, Y.J.; Kim, J.H.; Jang, S.C.; et al. EVpedia: An integrated database of high-throughput data for systemic analyses of extracellular vesicles. J. Extracell. Ves. 2013, 2, 20383. [Google Scholar] [CrossRef] [PubMed]
  114. Ferrari, G.; Garaguso, I.; Adu-Bobie, J.; Doro, F.; Taddei, A.R.; Biolchi, A.; Brunelli, B.; Giuliani, M.M.; Pizza, M.; Norais, N.; et al. Outer membrane vesicles from group B Neisseria meningitidis Δgna33 mutant: Proteomic and immunological comparison with detergent-derived outer membrane vesicles. Proteomics 2006, 6, 1856–1866. [Google Scholar] [CrossRef] [PubMed]
  115. Bernadac, A.; Gavioli, M.; Lazzaroni, J.C.; Raina, S.; Lloubès, R. Escherichia coli tol-pal mutants form outer membrane vesicles. J. Bacteriol. 1998, 180, 4872–4878. [Google Scholar] [CrossRef] [Green Version]
  116. Lommatzsch, J.; Templin, M.F.; Kraft, A.R.; Vollmer, W.; Höltje, J.V. Outer membrane localization of murein hydrolases: MltA, a third lipoprotein lytic transglycosylase in Escherichia coli. J. Bacteriol. 1997, 179, 5465–5470. [Google Scholar] [CrossRef] [Green Version]
  117. Oshida, T.; Sugai, M.; Komatsuzawa, H.; Hong, Y.M.; Suginaka, H.; Tomasz, A. A Staphylococcus aureus autolysin that has an N-acetylmuramoyl-L-alanine amidase domain and an endo-b-N-acetylglucosaminidase domain: Cloning, sequence analysis, and characterization. Proc. Natl. Acad. Sci. USA 1995, 92, 285–289. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Kolling, G.L.; Matthews, K.R. Export of virulence genes and Shiga toxin by membrane vesicles of Escherichia coli O157:H7. Appl. Environ. Microbiol. 1999, 65, 1843–1848. [Google Scholar] [CrossRef] [Green Version]
  119. Lee, E.Y.; Bang, J.Y.; Park, G.W.; Choi, D.S.; Kang, J.S.; Kim, H.J.; Park, K.S.; Lee, J.O.; Kim, Y.K.; Kwon, K.H. Global proteomic profiling of native outer membrane vesicles derived from Escherichia coli. Proteomics 2007, 7, 3143–3153. [Google Scholar] [CrossRef] [PubMed]
  120. Olofsson, A.; Vallström, A.; Petzold, K.; Tegtmeyer, N.; Schleucher, J.; Carlsson, S.; Haas, R.; Backert, S.; Wai, S.N.; Gröbner, G.; et al. Biochemical and functional characterization of Helicobacter pylori vesicles. Mol. Microbiol. 2010, 77, 1539–1555. [Google Scholar] [CrossRef] [Green Version]
  121. Kesty, N.C.; Kuehn, M.J. Incorporation of heterologous outer membrane and periplasmic proteins into Escherichia coli outer membrane vesicles. J. Biol. Chem. 2004, 279, 2069–2076. [Google Scholar] [CrossRef] [Green Version]
  122. Thay, B.; Wai, S.N.; Oscarsson, J. Staphylococcus aureus α-toxin-dependent induction of host cell death by membrane-derived vesicles. PLoS ONE 2013, 8, e54661. [Google Scholar] [CrossRef]
  123. Lee, E.Y.; Choi, D.Y.; Kim, D.K.; Kim, J.W.; Park, J.O.; Kim, S.; Kim, S.H.; Desiderio, D.M.; Kim, Y.K.; Kim, K.P. Gram-positive bacteria produce membrane vesicles: Proteomics-based characterization of Staphylococcus aureus-derived membrane vesicles. Proteomics 2009, 9, 5425–5436. [Google Scholar] [CrossRef]
  124. Choi, D.-S.; Kim, D.-K.; Choi, S.J.; Lee, J.; Choi, J.-P.; Rho, S.; Park, S.-H.; Kim, Y.-K.; Hwang, D.; Gho, Y.S. Proteomic analysis of outer membrane vesicles derived from Pseudomonas aeruginosa. Proteomics 2011, 11, 3424–3429. [Google Scholar] [CrossRef] [PubMed]
  125. Wai, S.N.; Lindmark, B.; Söderblom, T.; Takade, A.; Westermark, M.; Oscarsson, J.; Jass, J.; Richter-Dahlfors, A.; Mizunoe, Y.; Uhlin, B.E. Vesicle-mediated export and assembly of pore-forming oligomers of the enterobacterial ClyA cytotoxin. Cell 2003, 115, 25–35. [Google Scholar] [CrossRef] [Green Version]
  126. Bomberger, J.M.; Maceachran, D.P.; Coutermarsh, B.A.; Ye, S.; O’Toole, G.A.; Stanton, B.A. Long-distance delivery of bacterial virulence factors by Pseudomonas aeruginosa outer membrane vesicles. PLoS Path. 2009, 5, e1000382. [Google Scholar] [CrossRef] [Green Version]
  127. Ballok, A.E.; Filkins, L.M.; Bomberger, J.M.; Stanton, B.A.; O’Toole, G.A. Epoxide-mediated differential packaging of Cif and other virulence factors into outer membrane vesicles. J. Bacteriol. 2014, 196, 3633–3642. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  128. Hong, S.-W.; Choi, E.-B.; Min, T.-K.; Kim, J.-H.; Kim, M.-H.; Jeon, S.G.; Lee, B.-J.; Gho, Y.S.; Jee, Y.-K.; Pyun, B.-Y.; et al. An important role of α-hemolysin in extracellular vesicles on the development of atopic dermatitis induced by Staphylococcus aureus. PLoS ONE 2014, 9, e100499. [Google Scholar] [CrossRef] [PubMed]
  129. Horstman, A.L.; Kuehn, M.J. Enterotoxigenic Escherichia coli secretes active heat-labile enterotoxin via outer membrane vesicles. J. Biol. Chem. 2000, 275, 12489–12496. [Google Scholar] [CrossRef] [Green Version]
  130. Kadurugamuwa, J.L.; Beveridge, T.J. Bacteriolytic effect of membrane vesicles from Pseudomonas aeruginosa on other bacteria including pathogens: Conceptually new antibiotics. J. Bacteriol. 1996, 178, 2767–2774. [Google Scholar] [CrossRef] [Green Version]
  131. Vasilyeva, N.V.; Tsfasman, I.M.; Suzina, N.E.; Stepnaya, O.A.; Kulaev, I.S. Secretion of bacteriolytic endopeptidaseL5 of Lysobacter sp. XL1 into the medium by means of outer membrane vesicles. FEBS J. 2008, 275, 3827–3835. [Google Scholar] [CrossRef]
  132. Nevot, M.; Deroncelé, V.; Messner, P.; Guinea, J.; Mercadé, E. Characterization of outer membrane vesicles released by the psychrotolerant bacterium Pseudoalteromonas antarctica NF3. Environ. Microbiol. 2006, 8, 1523–1533. [Google Scholar] [CrossRef] [Green Version]
  133. Lappann, M.; Otto, A.; Becher, D.; Vogel, U. Comparative proteome analysis of spontaneous outer membrane vesicles and purified outer membranes of Neisseria meningitidis. J. Bacteriol. 2013, 195, 4425–4435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Olczak, T.; Wójtowicz, H.; Ciuraszkiewicz, J.; Olczak, M. Species specificity, surface exposure, protein expression, immunogenicity, and participation in biofilm formation of Porphyromonas gingivalis HmuY. BMC Microbiol. 2010, 10, 134. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Ellis, T.N.; Leiman, S.A.; Kuehn, M.J. Naturally produced outer membrane vesicles from Pseudomonas aeruginosa elicit a potent innate immune response via combined sensing of both lipopolysaccharide and protein components. Infect. Immun. 2010, 78, 3822–3831. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  136. Prados-Rosales, R.; Baena, A.; Martinez, L.R.; Luque-Garcia, J.; Kalscheuer, R.; Veeraraghavan, U.; Camara, C.; Nosanchuk, J.D.; Besra, G.S.; Chen, B.; et al. Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. J. Clin. Invest. 2011, 121, 1471–1483. [Google Scholar] [CrossRef]
  137. Kothary, M.H.; Gopinath, G.R.; Gangiredla, J.; Rallabhandi, P.V.; Harrison, L.M.; Yan, Q.Q.; Chase, H.R.; Lee, B.; Park, E.; Yoo, Y.; et al. Analysis and characterization of proteins associated with outer membrane vesicles secreted by Cronobacter spp. Front. Microbiol. 2017, 8, 134. [Google Scholar] [CrossRef] [Green Version]
  138. Stumpe, S.; Schmid, R.; Stephens, D.L.; Georgiou, G.; Bakker, E.P. Identification of OmpT as the protease that hydrolyzes the antimicrobial peptide protamine before it enters growing cells of Escherichia coli. J. Bacteriol. 1998, 180, 4002–4006. [Google Scholar] [CrossRef] [Green Version]
  139. Bergman, M.A.; Cummings, L.A.; Barrett, S.L.R.; Smith, K.D.; Lara, J.C.; Aderem, A.; Cookson, B.T. CD4+ T cells and toll-like receptors recognize Salmonella antigens expressed in bacterial surface organelles. Infect. Immun. 2005, 73, 1350–1356. [Google Scholar] [CrossRef] [Green Version]
  140. Kwon, S.-O.; Gho, Y.S.; Lee, J.C.; Kim, S.I. Proteome analysis of outer membrane vesicles from a clinical Acinetobacter baumannii isolate. Fems Microbiol. Lett. 2009, 297, 150–156. [Google Scholar] [CrossRef]
  141. Bauman, S.J.; Kuehn, M.J. Purification of outer membrane vesicles from Pseudomonas aeruginosa and their activation of an IL-8 response. Microb. Infect. 2006, 8, 2400–2408. [Google Scholar] [CrossRef] [Green Version]
  142. Olaya-Abril, A.; Prados-Rosales, R.; McConnell, M.J.; Martín-Peña, R.; González-Reyes, J.A.; Jiménez-Munguía, I.; Gómez-Gascón, L.; Fernández, J.; Luque-García, J.L.; García-Lidón, C.; et al. Characterization of protective extracellular membrane-derived vesicles produced by Streptococcus pneumoniae. J. Proteom. 2014, 106, 46–60. [Google Scholar] [CrossRef]
  143. Park, A.J.; Surette, M.D.; Khursigara, C.M. Antimicrobial targets localize to the extracellular vesicle-associated proteome of Pseudomonas aeruginosa grown in a biofilm. Front. Microbiol. 2014, 5, 464. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Aguilera, L.; Toloza, L.; Giménez, R.; Odena, A.; Oliveira, E.; Aguilar, J.; Badia, J.; Baldomà, L. Proteomic analysis of outer membrane vesicles from the probiotic strain Escherichia coli nissle 1917. Proteomics 2014, 14, 222–229. [Google Scholar] [CrossRef] [PubMed]
  145. Brown, L.; Kessler, A.; Cabezas-Sanchez, P.; Luque-Garcia, J.L.; Casadevall, A. Extracellular vesicles produced by the Gram-positive bacterium Bacillus subtilis are disrupted by the lipopeptide surfactin. Mol. Microbiol. 2014, 93, 183–198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Lee, E.-Y.; Choi, D.-S.; Kim, K.-P.; Gho, Y.S. Proteomics in gram-negative bacterial outer membrane vesicles. Mass Spectrom. Rev. 2008, 27, 535–555. [Google Scholar] [CrossRef] [PubMed]
  147. Galka, F.; Wai, S.N.; Kusch, H.; Engelmann, S.; Hecker, M.; Schmeck, B.; Hippenstiel, S.; Uhlin, B.E.; Steinert, M. Proteomic characterization of the whole secretome of Legionella pneumophila and functional analysis of outer membrane vesicles. Infect. Immun. 2008, 76, 1825–1836. [Google Scholar] [CrossRef] [Green Version]
  148. Moon, D.C.; Choi, C.H.; Lee, J.H.; Choi, C.-W.; Kim, H.-Y.; Park, J.S.; Kim, S.I.; Lee, J.C. Acinetobacter baumannii outer membrane protein a modulates the biogenesis of outer membrane vesicles. J. Microbiol. 2012, 50, 155–160. [Google Scholar] [CrossRef]
  149. Tong, T.T.; Mörgelin, M.; Forsgren, A.; Riesbeck, K. Haemophilus influenzae survival during complement-mediated attacks is promoted by Moraxella catarrhalis outer membrane vesicles. J. Infect. Dis. 2007, 195, 1661–1670. [Google Scholar]
  150. Jang, K.-S.; Sweredoski, M.J.; Graham, R.L.J.; Hess, S.; Clemons, W.M. Comprehensive proteomic profiling of outer membrane vesicles from Campylobacter jejuni. J. Proteom. 2014, 98, 90–98. [Google Scholar] [CrossRef] [Green Version]
  151. Veith, P.D.; Chen, Y.-Y.; Gorasia, D.G.; Chen, D.; Glew, M.D.; O’Brien-Simpson, N.M.; Cecil, J.D.; Holden, J.A.; Reynolds, E.C. Porphyromonas gingivalis outer membrane vesicles exclusively contain outer Membrane and periplasmic proteins and carry a cargo enriched with virulence factors. J. Proteome Res. 2014, 13, 2420–2432. [Google Scholar] [CrossRef]
  152. Dorward, D.W.; Schwan, T.G.; Garon, C.F. Immune capture and detection of Borrelia burgdorferi antigens in urine, blood, or tissues from infected ticks, mice, dogs, and humans. J. Clin. Microbiol. 1991, 29, 1162–1170. [Google Scholar] [CrossRef] [Green Version]
  153. Kadurugamuwa, J.L.; Beveridge, T.J. Delivery of the non-membrane-permeative antibiotic gentamicin into mammalian cells by using Shigella flexneri membrane vesicles. Antimicrob. Agents Chemother. 1998, 42, 1476–1483. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Fiocca, R.; Necchi, V.; Sommi, P.; Ricci, V.; Telford, J.; Cover, T.L.; Solcia, E. Release of Helicobacter pylori vacuolating cytotoxin by both a specific secretion pathway and budding of outer membrane vesicles. Uptake of released toxin and vesicles by gastric epithelium. J. Pathol. 1999, 188, 220–226. [Google Scholar] [CrossRef]
  155. Post, D.M.B.; Zhang, D.; Eastvold, J.S.; Teghanemt, A.; Gibson, B.W.; Weiss, J.P. Biochemical and functional characterization of membrane blebs purified from Neisseria meningitidis serogroup B. J. Biol. Chem. 2005, 280, 38383–38394. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  156. Kim, J.H.; Lee, J.; Park, J.; Gho, Y.S. Gram-negative and Gram-positive bacterial extracellular vesicles. Semin. Cell Dev. Biol. 2015, 40, 97–104. [Google Scholar] [CrossRef]
  157. Ollinger, J.; Bowen, B.; Wiedmann, M.; Boor, K.J.; Bergholz, T.M. Listeria monocytogenes sigmaB modulates PrfA-mediated virulence factor expression. Infect. Immun. 2009, 77, 2113–2124. [Google Scholar] [CrossRef] [Green Version]
  158. Altindis, E.; Fu, Y.; Mekalanos, J.J. Proteomic analysis of Vibrio cholerae outer membrane vesicles. Proc. Natl. Acad. Sci. USA 2014, 111, E1548–E1556. [Google Scholar] [CrossRef] [Green Version]
  159. Allan, N.D.; Kooi, C.; Sokol, P.A.; Beveridge, T.J. Putative virulence factors are released in association with membrane vesicles from Burkholderia cepacia. Can. J. Microbiol. 2003, 49, 613–624. [Google Scholar] [CrossRef]
  160. Cossart, P.; Vicente, M.F.; Mengaud, J.; Baquero, F.; Perez-Diaz, J.C.; Berche, P. Listeriolysin O is essential for virulence of Listeria monocytogenes: Direct evidence obtained by gene complementation. Infect. Immun. 1989, 57, 3629–3636. [Google Scholar] [CrossRef] [Green Version]
  161. Hozbor, D.; Rodriguez, M.E.; Fernández, J.; Lagares, A.; Guiso, N.; Yantorno, O. Release of outer membrane vesicles from Bordetella pertussis. Curr. Microbiol. 1999, 38, 273–278. [Google Scholar] [CrossRef]
  162. Lee, J.C. Staphylococcus aureus membrane vesicles and Its potential role in bacterial pathogenesis. J. Bacteriol. Virol. 2012, 42, 181–188. [Google Scholar] [CrossRef] [Green Version]
  163. Roberts, C.A.; Buikstra, J.E. Bacterial infections. In Ortner’s Identification of Pathological Conditions in Human Skeletal Remains; Buikstra, J.E., Ed.; Academic Press: Cambridge, MA, USA, 2019; pp. 321–439. [Google Scholar]
  164. Lim, S.; Yoon, H. Roles in outer membrane vesicles (OMVs) in bacterial virulence. J. Bacteriol. Virol. 2015, 45, 1–10. [Google Scholar] [CrossRef] [Green Version]
  165. Schulz, E.; Goes, A.; Garcia, R.; Panter, F.; Koch, M.; Müller, R.; Fuhrmann, K.; Fuhrmann, G. Biocompatible bacteria-derived vesicles show inherent antimicrobial activity. J. Control. Release 2018, 290, 46–55. [Google Scholar] [CrossRef] [PubMed]
  166. Kovar, M.; Boyman, O.; Shen, X.; Hwang, I.; Kohler, R.; Sprent, J. Direct stimulation of T cells by membrane vesicles from antigen-presenting cells. Proc. Natl. Acad. Sci. USA 2006, 103, 11671–11676. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Muralinath, M.; Kuehn, M.J.; Roland, K.L.; Curtiss, R., 3rd. Immunization with Salmonella enterica serovar Typhimurium-derived outer membrane vesicles delivering the pneumococcal protein PspA confers protection against challenge with Streptococcus pneumoniae. Infect. Immun. 2011, 79, 887–894. [Google Scholar] [CrossRef] [Green Version]
  168. Schroeder, J.; Aebischer, T. Recombinant outer membrane vesicles to augment antigen-specific live vaccine responses. Vaccine 2009, 27, 6748–6754. [Google Scholar] [CrossRef]
  169. Kim, S.H.; Kim, K.S.; Lee, S.R.; Kim, E.; Kim, M.S.; Lee, E.Y.; Gho, Y.S.; Kim, J.W.; Bishop, R.E.; Chang, K.T. Structural modifications of outer membrane vesicles to refine them as vaccine delivery vehicles. Biochim. Biophys. Acta 2009, 1788, 2150–2159. [Google Scholar] [CrossRef] [Green Version]
  170. Chen, D.J.; Osterrieder, N.; Metzger, S.M.; Buckles, E.; Doody, A.M.; DeLisa, M.P.; Putnam, D. Delivery of foreign antigens by engineered outer membrane vesicle vaccines. Proc. Natl. Acad. Sci. USA 2010, 107, 3099–3104. [Google Scholar] [CrossRef] [Green Version]
  171. Embry, A.; Meng, X.; Cantwell, A.; Dube, P.H.; Xiang, Y. Enhancement of immune response to an antigen delivered by vaccinia virus by displaying the antigen on the surface of intracellular mature virion. Vaccine 2011, 29, 5331–5339. [Google Scholar] [CrossRef] [Green Version]
  172. Persson, G.; Pors, S.E.; Thøfner, I.C.N.; Bojesen, A.M. Vaccination with outer membrane vesicles and the fimbrial protein FlfA offers improved protection against lesions following challenge with Gallibacterium anatis. Vet. Microbiol. 2018, 217, 104–111. [Google Scholar] [CrossRef]
  173. Schaar, V.; Paulsson, M.; Mörgelin, M.; Riesbeck, K. Outer membrane vesicles shield Moraxella catarrhalis β-lactamase from neutralization by serum IgG. J. Antimicrob. Chemother. 2013, 68, 593–600. [Google Scholar] [CrossRef] [Green Version]
  174. Stevenson, T.C.; Cywes-Bentley, C.; Moeller, T.D.; Weyant, K.B.; Putnam, D.; Chang, Y.-F.; Jones, B.D.; Pier, G.B.; DeLisa, M.P. Immunization with outer membrane vesicles displaying conserved surface polysaccharide antigen elicits broadly antimicrobial antibodies. Proc. Natl. Acad. Sci. USA 2018, 115, E3106–E3115. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  175. Huang, W.; Wang, S.; Yao, Y.; Xia, Y.; Yang, X.; Li, K.; Sun, P.; Liu, C.; Sun, W.; Bai, H.; et al. Employing Escherichia coli-derived outer membrane vesicles as an antigen delivery platform elicits protective immunity against Acinetobacter baumannii infection. Sci. Rep. 2016, 6, 37242. [Google Scholar] [CrossRef] [PubMed]
  176. Roier, S.; Leitner, D.R.; Iwashkiw, J.; Schild-Prufert, K.; Feldman, M.F.; Krohne, G.; Reidl, J.; Schild, S. Intranasal immunization with nontypeable Haemophilus influenzae outer membrane vesicles induces cross-protective immunity in mice. PLoS ONE 2012, 7, e42664. [Google Scholar] [CrossRef]
  177. Roier, S.; Fenninger, J.C.; Leitner, D.R.; Rechberger, G.N.; Reidl, J.; Schild, S. Immunogenicity of Pasteurella multocida and Mannheimia haemolytica outer membrane vesicles. Int. J. Med. Microbiol. 2013, 303, 247–256. [Google Scholar] [CrossRef] [PubMed]
  178. Petersen, H.; Nieves, W.; Russell-Lodrigue, K.; Roy, C.J.; Morici, L.A. Evaluation of a Burkholderia pseudomallei Outer Membrane Vesicle Vaccine in Nonhuman Primates. Procedia Vaccinol 2014, 8, 38–42. [Google Scholar] [CrossRef] [Green Version]
  179. Choi, H.-I.; Kim, M.; Jeon, J.; Han, J.K.; Kim, K.-S. Overexpression of MicA induces production of OmpC-enriched outer membrane vesicles that protect against Salmonella challenge. Biochem. Biophys. Res. Commun. 2017, 490, 991–996. [Google Scholar] [CrossRef]
  180. Acevedo, R.; Fernandez, S.; Zayas, C.; Acosta, A.; Sarmiento, M.; Ferro, V.; Rosenqvist, E.; Campa, C.; Cardoso, D.; Garcia, L.; et al. Bacterial outer membrane vesicles and vaccine applications. Front. Immunol. 2014, 5, 121. [Google Scholar] [CrossRef] [Green Version]
  181. Fuhrmann, G.; Neuer, A.L.; Herrmann, I.K. Extracellular vesicles – A promising avenue for the detection and treatment of infectious diseases? Eur. J. Pharm. Biopharm. 2017, 118, 56–61. [Google Scholar] [CrossRef]
  182. Tan, K.; Li, R.; Huang, X.; Liu, Q. Outer membrane vesicles: Current status and future direction of these novel vaccine adjuvants. Front. Microbiol. 2018, 9, 783. [Google Scholar] [CrossRef] [Green Version]
  183. Edelman, R. Vaccine adjuvants. Rev. Infect. Dis. 1980, 2, 370–383. [Google Scholar] [CrossRef]
  184. Exley, C. Aluminium adjuvants and adverse events in sub-cutaneous allergy immunotherapy. AllergyAsthma Clin. Immunol. 2014, 10, 1–5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  185. Lee, J.; Yoo, J.K.; Sohn, H.J.; Kang, H.K.; Kim, D.; Shin, H.J.; Kim, J.H. Protective immunity against Naegleria fowleri infection on mice immunized with the rNfa1 protein using mucosal adjuvants. Parasitol. Res. 2015, 114, 1377–1385. [Google Scholar] [CrossRef] [PubMed]
  186. Mutsch, M.; Zhou, W.; Rhodes, P.; Bopp, M.; Chen, R.T.; Linder, T.; Spyr, C.; Steffen, R. Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N. Engl. J. Med. 2004, 350, 896–903. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  187. Sierra, G.V.; Campa, H.C.; Varcacel, N.M.; Garcia, I.L.; Izquierdo, P.L.; Sotolongo, P.F.; Casanueva, G.V.; Rico, C.O.; Rodriguez, C.R.; Terry, M.H. Vaccine against group B Neisseria meningitidis: Protection trial and mass vaccination results in Cuba. Niph Ann. 1991, 14, 195–207. [Google Scholar]
  188. Haneberg, B.; Dalseg, R.; Oftung, F.; Wedege, E.; Hoiby, E.A.; Haugen, I.; Holst, J.; Andersen, S.; Aase, A.; Naess, L.; et al. Towards a nasal vaccine against meningococcal disease, and prospects for its use as a mucosal adjuvant. Dev. Biol. Stand. 1998, 92, 127–133. [Google Scholar]
  189. Estevez, F.; Carr, A.; Solorzano, L.; Valiente, O.; Mesa, C.; Barroso, O.; Sierra, G.V.; Fernandez, L.E. Enhancement of the immune response to poorly immunogenic gangliosides after incorporation into very small size proteoliposomes (VSSP). Vaccine 1999, 18, 190–197. [Google Scholar] [CrossRef]
  190. Sardinas, G.; Reddin, K.; Pajon, R.; Gorringe, A. Outer membrane vesicles of Neisseria lactamica as a potential mucosal adjuvant. Vaccine 2006, 24, 206–214. [Google Scholar] [CrossRef]
  191. Gurung, M.; Moon, D.C.; Choi, C.W.; Lee, J.H.; Bae, Y.C.; Kim, J.; Lee, Y.C.; Seol, S.Y.; Cho, D.T.; Kim, S.I.; et al. Staphylococcus aureus produces membrane-derived vesicles that induce host cell death. PLoS ONE 2011, 6, e27958. [Google Scholar] [CrossRef] [Green Version]
  192. Yuan, J.; Yang, J.; Hu, Z.; Yang, Y.; Shang, W.; Hu, Q.; Zheng, Y.; Peng, H.; Zhang, X.; Cai, X.; et al. Safe Staphylococcal Platform for the Development of Multivalent Nanoscale Vesicles against Viral Infections. Nano Lett. 2018, 18, 725–733. [Google Scholar] [CrossRef] [Green Version]
  193. Diaz-Garrido, N.; Fábrega, M.-J.; Vera, R.; Giménez, R.; Badia, J.; Baldomà, L. Membrane vesicles from the probiotic Nissle 1917 and gut resident Escherichia coli strains distinctly modulate human dendritic cells and subsequent T cell responses. J. Funct. Foods 2019, 61, 103495. [Google Scholar] [CrossRef]
  194. Kim, M.H.; Choi, S.J.; Choi, H.I.; Choi, J.P.; Park, H.K.; Kim, E.K.; Kim, M.J.; Moon, B.S.; Min, T.K.; Rho, M.; et al. Lactobacillus plantarum-derived Extracellular Vesicles Protect Atopic Dermatitis Induced by Staphylococcus aureus-derived Extracellular Vesicles. Allergy Asthma Immunol. Res. 2018, 10, 516–532. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Structural characteristics of Gram-negative (A) and Gram-positive (B) bacterial membrane vesicles.
Figure 1. Structural characteristics of Gram-negative (A) and Gram-positive (B) bacterial membrane vesicles.
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Figure 2. Physiological and pathological functions of bacterial membrane vesicles.
Figure 2. Physiological and pathological functions of bacterial membrane vesicles.
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Table
Table 1. Specific components of bacterial membrane vesicles (BMVs) as targets for antibiotics.
Table 1. Specific components of bacterial membrane vesicles (BMVs) as targets for antibiotics.
BacteriumReceptorLigandReference
Staphylococcus aureus; Enterococcus faecalis; Streptococcus spp.Monomeric membrane phospholipidsDaptomycin, nisin, pexiganan, melittin[62,63]
Escherichia coliLipid and proteinPolymyxin B and E[64,65]
Moraxella catarrhalis; Escherichia coliHydrolytic enzymesAmoxicillin, cefaclor
Melittin, penicillin, methicillin		[66]
[67,68]
Burkholderia cenocepaciaHydrophobic lipocalinsRifampicin, norfloxacin, ceftazidime, polymyxin B[60]
Pseudomonas aeruginosa; Streptococcus pneumoniae; Klebsiella pneumoniaeCapsular polysaccharidesPolymyxin B[69,70,71,72,73]
Pseudomonas aeruginosa; Staphylococcus epidermidis; Haemophilus influenzaeeDNAKanamycin, tobramycin, vancomycin, human β-defensin-3, gentamicin, amikacin [70,74,75]
Table
Table 2. Genetic materials in bacterial membrane vesicles (BMVs).
Table 2. Genetic materials in bacterial membrane vesicles (BMVs).
Genetic MaterialSpeciesReference
Chromosomal DNAEscherichia coli[91]
Clostridium perfringens[96]
Neisseria gonorrhoeae[12]
Porphyromonas gingivalis[97]
Prochlorococcus sp.[98]
Ruminococcus spp.[87]
Shewanella vesiculosa[99]
Mycobacterium tuberculosis[100]
Streptococcus mutans[101]
Plasmid DNAAcinetobacter baumanni[94]
Acinetobacter baylyi[89]
Escherichia coli[102]
Pseudomonas aeruginosa[93]
Neisseria gonorrhoeae[12]
Viral DNAEscherichia coli[102]
Not specified DNAAcholeplasma laidlawii[103]
mRNAEscherichia coli[95]
Porphyromonas gingivalis[97]
rRNAEscherichia coli[95]
Porphyromonas gingivalis[97]
sRNAEscherichia coli[95]
Vibrio cholera[90]
Clostridium perfringens[96]
Mycobacterium tuberculosis[100]
Listeria monocytogenes[104]
tRNAEscherichia coli[95]
Not specified RNANeisseria gonorrhoeae[12]
Table
Table 3. Protein families identified by proteomic analyses of BMVs.
Table 3. Protein families identified by proteomic analyses of BMVs.
ProteinsFunctionSpeciesReference
Outer membrane porins
OmpA and OmpXBinding to host cell receptorsCronobacter sakazakii[137]
Cronobacter turicensis[137]
Cronobacter malonaticus[137]
OmpA, OmpC, and OmpFBinding to host cells Escherichia coli[119]
Escherichia coli△tolR[138]
OmpCPore-forming activitySalmonella typhi[139]
AbOmpABinding to host tissueAcinetobacter baumannii[140]
OprE and OprFPorinPseudomonas aeruginosa[141]
Pseudoalteromonas antarctica NF3[132]
PorA and PorBAdherence to host cellsNeisseria meningitis[133]
Neisseria meningitis △gna33[114]
PspABinding to human lactoferrinStreptococcus pneumoniae[142]
Antibiotic resistance
β-lactamaseβ-lactamase activityPseudomonas aeruginosa[78]
Streptococcus pneumoniae[108]
Moraxella catarrhalis[66]
Carbapenemase Hydrolysis of carbapenemAcinetobacter baumannii[89]
Cephalosporinasesβ-lactamase activityBacteroides spp.[107]
Penicillin-binding proteinsPeptidoglycan-based cell
wall biogenesis		Streptococcus pneumoniae[123]
TolCMultidrug efflux pumpsEscherichia coli[67]
Escherichia coli△tolR[138]
MexMultidrug efflux pumpsPseudomonas aeruginosa[143]
Pseudoalteromonas antarctica NF3[132]
MtrMultidrug efflux pumpsNeisseria meningitis[133]
Neisseria meningitis△gna33[114]
ABC Transporters
BtuBVitamin B12 TransporterEscherichia coli[144]
Escherichia coli△tolR[138]
TsxNucleoside-specific channel-forming proteinEscherichia coli[119]
Escherichia coli△tolR[138]
FecA, FhuA, FhuE, FiuA, FptASiderophore transporterNeisseria meningitis△gna33[114]
Escherichia coli[144]
Clostridium perfringens[96]
Bacillus subtilis[145]
Escherichia coli△tolR[138]
FadLLong-chain fatty acid transporterEscherichia coli[119]
Escherichia coli△tolR[138]
Maltoporin LamBABC TransportersPseudoalteromonas antarctica NF3[119]
Escherichia coli△tolR[138]
Escherichia coli[144]
ArtI, BraC, FliY, GlnH, HisJAmino acid transporterNeisseria meningitis[133]
Maltose/maltodextrinSugar transporterStreptococcus pneumoniae
Sugar ABC transporter [142]
Motility-related proteins
Pilus-associated proteinMotility-related proteinsNeisseria meningitis[133]
Neisseria meningitis△gna33[114]
Flagellin FliCMotility-related proteinsPseudoalteromonas antarctica NF3[132]
Escherichia coli[144]
Pseudomonas aeruginosa[146]
Protease/chaperone
MSPProteaseLegionella pneumophila[147]
Protease PlaToxicityYersinia pestis[79]
ProteasesEnzyme activityStreptococcus pneumoniae[142]
Acinetobacter baumanni[148]
Yersinia pestis[79]
Chaperone SurAChaperonePseudoalteromonas antarctica NF3[132]
ChaperoneEscherichia coli[144]
ChaperoneEscherichia coli△tolR[138]
Tail-specific peptidase PrcProteaseEscherichia coli[144]
ProteaseNeisseria meningitis△gna33[114]
Protease DegQProteasePseudoalteromonas antarctica NF3[146]
ProteaseEscherichia coli△tolR[146]
ProteaseEscherichia coli[144]
Adhesion/invasion
F1 outer fimbrial antigenComplement bindingYersinia pestis[79]
Adhesin AilAdhesionYersinia pestis[79]
UspA1, UspA2Complement bindingMoraxella catarrhalis[149]
CDTToxicity, invasionCampylobacter jejuni[150]
RgpA, RgpB, KqpHost tissue invasionPorphyromonas gingivalis[151]
Opacity proteinAdhesion and invasionNeisseria meningitis[133]
OspA, OspB, OspDAdherence to host cellsBorrelia burgdorferi[152]
IpaB, C, DInvasion of plasmid antigensShigellaflexneri[153]
Staphopain AInvasionStreptococcus pneumoniae[108]
SabAAdherenceHelicobacter pylori[154]
Killing of competing bacteria
Endopeptidase L5Peptidoglycan hydrolyseLysobacter sp.[131]
N-acetylmuramoyl-L-alanine amidasePeptidoglycan hydrolyseStreptococcus pneumoniae[117]
SLTMurein hydrolysesNeisseria meningitis[155]
Neisseria meningitis△gna33[132]
Escherichia coli△tolR[119]
Escherichia coli[138]
MltMurein hydrolyseNeisseria meningitis[155]
Pseudoalteromonas antarctica NF3[114]
Escherichia coli△tolR[119]
Escherichia coli[138]
Host cell modulation
α-HemolysinHemolysisPseudomonas aeruginosa[153]
Pseudoalteromonas antarctica NF3[132]
Staphylococcus aureus[128]
Neisseria meningitis△gna33[114]
Cytolysin A (ClyA)Pore-forming abilityEnterohemorrhagic E. coli[125]
Salmonella typhi[125]
Heat labile enterotoxin (LT)ToxicityEnterotoxigenic E. coli[129]
Shiga toxin (Stx)ToxicityShiga toxin producing E. coli[13]
ToxicityShigella dysenteriae[13]
CifDecrease of apical CFTR expressionPseudomonas aeruginosa[127]
VacAVacuolating activityHelicobacter pylori[154]
ProteolysinProteolysisStreptococcus pneumoniae[156]
β2 toxinToxicityStreptococcus mutans[156]
SEQ, SSaA1, and SSaA2Evade the host immune systemStreptococcus pneumoniae[123]
Lmo2785CatalaseListeria monocytogenes[157]
SODImmunomodulatory effectAcinetobacter baumannii[140]
Virulence factors
Phospholipase C ProteaseHydrolyzes of phospholipidsPseudomonas aeruginosa[13]
HcpAdherenceHelicobacter pylori[154]
Rtx toxinCytotoxicity, depolymerizing actinVibrio cholera[158]
Macrophage infectivity potentiator (MIP)CytotoxicityNeisseria meningitis[133]
Neisseria meningitis△gna33[114]
HemagglutininEnzyme activitiesBurkholderia cepacia[159]
IgA proteaseProtease activityNeisseria meningitis[133]
Pseudoalteromonas antartica NF3[132]
InlB and LLO8Cellular invasionListeria monocytogenes[160]
Pertussis toxin (Ptx), CytotoxicityBordetella pertussis[161]
Adenylate cyclase, hemolysin
SbIIgG-binding proteinStaphylococcus aureus[162]
Protective antigen, ToxicityBacillus anthracis[110]
Lethal factor, Edema toxin
Anthrolysin
Cytoplasmic proteins
GroEL60 KDa chaperoninNeisseria meningitis[133]
Escherichia coli[144]
ATP-dependent DNA helicaseInteractionStaphylococcus aureus[123]
EF-TuElongation factorNeisseria meningitis[133]
Staphylococcus aureus[123]
Clostridium perfringens[96]
Pyruvate kinase GlycolysisStaphylococcus aureus[123]
Acetate kinase PhosphorylationStaphylococcus aureus[123]
Type-3 secretion proteinsCytoplasmic proteinsAcinetobacter baumannii[140]
Alkaline phosphataseIn vitro enzyme activitiesPseudomonas aeruginosa[143]
DNA gyrase subunit AStimulate to antibioticsStaphylococcus aureus[123]
Hsp60Heat shock proteinLegionella pneumophila[13]
DnaKHeat shock 70 kDa proteinNeisseria meningitis△gna33[114]
30S ribosomal protein S1 (RpsA)Cytoplasmic proteinsNeisseria meningitis△gna33[114]
Cytoplasmic proteinsEscherichia coli[144]
50S ribosomal protein L7/L12 (RplL)Cytoplasmic proteinsEscherichia coli[144]
Coagulation
Staphylocoagulase precursor [COL]coagulationStaphylococcus aureus[123]
Staphylocoagulase precursorcoagulationStaphylococcus aureus[123]
Truncated secreted von WillebrandcoagulationStaphylococcus aureus[123]
Factor-binding protein VWbpcoagulationStaphylococcus aureus[123]
Others
IssIncreased serum survival Escherichia coli[144]
OstAOrganic solvent tolerance proteinPseudoalteromonas antartica NF3[132]
Organic solvent tolerance proteinEscherichia coli△tolR[138]
Organic solvent tolerance proteinEscherichia coli[144]
NADH dehydrogenase-like proteinOxidation reductionStaphylococcus aureus[123]

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Uddin, M.J.; Dawan, J.; Jeon, G.; Yu, T.; He, X.; Ahn, J. The Role of Bacterial Membrane Vesicles in the Dissemination of Antibiotic Resistance and as Promising Carriers for Therapeutic Agent Delivery. Microorganisms 2020, 8, 670. https://doi.org/10.3390/microorganisms8050670

AMA Style

Uddin MJ, Dawan J, Jeon G, Yu T, He X, Ahn J. The Role of Bacterial Membrane Vesicles in the Dissemination of Antibiotic Resistance and as Promising Carriers for Therapeutic Agent Delivery. Microorganisms. 2020; 8(5):670. https://doi.org/10.3390/microorganisms8050670

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Uddin, Md Jalal, Jirapat Dawan, Gibeom Jeon, Tao Yu, Xinlong He, and Juhee Ahn. 2020. "The Role of Bacterial Membrane Vesicles in the Dissemination of Antibiotic Resistance and as Promising Carriers for Therapeutic Agent Delivery" Microorganisms 8, no. 5: 670. https://doi.org/10.3390/microorganisms8050670

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