Antibacterial Resistance and Novel Therapeutic Strategies

A special issue of Antibiotics (ISSN 2079-6382).

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 20733

Special Issue Editors


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Guest Editor
Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
Interests: Burkholderia cepacia complex; antimicrobials; bacterial virulence; immunoproteomics; immunotherapeutic strategies
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Co-Guest Editor
Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden
Interests: anti-microbial products; host-pathogen interactions; epigenetics; environmental cues; innate immune memory; aquatic environment; aquaculture

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Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland
Interests: pathogenesis of tuberculosis (TB); develop novel anti-TB drugs targeting alternate pathways of Mycobacterium tuberculosis
Special Issues, Collections and Topics in MDPI journals

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Co-Guest Editor
Department of Animal Health, University of León, 24071 León, Spain
Interests: veterinary pathology; microbiology; porcine respiratory disease complex; antimicrobial resistance; vaccines; immune response; immunohistochemistry
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Special Issue Information

Dear Colleagues,

Bacterial human infectious diseases remains a serious threat to public health worldwide. In addition, the emergence of bacterial resistance to the clinically in-use antimicrobials lowers the efficacy of available prevention and treatment measures, leading to extended hospitalization periods and causing a severe financial burden to healthcare systems worldwide. Therefore, development of novel antibiotics with chemical characteristics distinct from those already available commercially is urgently required. Additionally, to avoid antimicrobial resistance, antibiotics with novel modes of action or interacting targets distinct from those which are clinically in use will be the most interesting to explore.

Another problem associated with antimicrobial resistance is the formation of antibiotic persisters. Therefore, more studies are needed about the molecular pathways involved in the formation and survival of persisters, in order to develop new therapeutic strategies to eliminate them.

In this Special Issue of Antibiotics, we invite authors to submit articles concerning any aspects related to the development of new antibacterial agents and/or their mechanism of action.

Additionally, this Special Issue welcome studies about bacterial resistance to antibiotics and antibiotic persisters.

Dr. Sílvia A. Sousa
Dr. Norouzitallab Parisa
Dr. Ashok Aspatwar
Dr. Sonia Martinez
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • novel antibacterial agents
  • antibacterial targets
  • mechanisms of antibiotic resistance
  • antibiotic persisters
  • mechanisms for formation and survival of persisters

Published Papers (6 papers)

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Research

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21 pages, 7932 KiB  
Article
Artemisia brevifolia Wall. Ex DC Enhances Cefixime Susceptibility by Reforming Antimicrobial Resistance
by Aroosa Zafar, Yusra Wasti, Muhammad Majid, Durdana Muntaqua, Simona Gabriela Bungau and Ihsan ul Haq
Antibiotics 2023, 12(10), 1553; https://doi.org/10.3390/antibiotics12101553 - 20 Oct 2023
Viewed by 1768
Abstract
(1) Background: A possible solution to antimicrobial resistance (AMR) is synergism with plants like Artemisia brevifolia Wall. ex DC. (2) Methods: Phytochemical quantification of extracts (n-hexane (NH), ethyl acetate (EA), methanol (M), and aqueous (Aq)) was performed using RP-HPLC and chromogenic assays. Extracts [...] Read more.
(1) Background: A possible solution to antimicrobial resistance (AMR) is synergism with plants like Artemisia brevifolia Wall. ex DC. (2) Methods: Phytochemical quantification of extracts (n-hexane (NH), ethyl acetate (EA), methanol (M), and aqueous (Aq)) was performed using RP-HPLC and chromogenic assays. Extracts were screened against resistant clinical isolates via disc diffusion, broth dilution, the checkerboard method, time–kill, and protein quantification assays. (3) Results: M extract had the maximum phenolic (15.98 ± 0.1 μg GAE/mgE) and flavonoid contents (9.93 ± 0.5 μg QE/mgE). RP-HPLC displayed the maximum polyphenols in the M extract. Secondary metabolite determination showed M extract to have the highest glycosides, alkaloids, and tannins. Preliminary resistance profiling indicated that selected isolates were resistant to cefixime (MIC 20–40 µg/mL). Extracts showed moderate antibacterial activity (MIC 60–100 µg/mL). The checkerboard method revealed a total synergy between EA extract and cefixime with 10-fold reductions in cefixime dose against resistant P. aeruginosa and MRSA. Moreover, A. brevifolia extracts potentiated the antibacterial effect of cefixime after 6 and 9 h. The synergistic combination was non- to slightly hemolytic and could inhibit bacterial protein in addition to cefixime disrupting the cell wall, thus making it difficult for bacteria to survive. (4) Conclusion: A. brevifolia in combination with cefixime has the potential to inhibit AMR. Full article
(This article belongs to the Special Issue Antibacterial Resistance and Novel Therapeutic Strategies)
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23 pages, 2961 KiB  
Article
Inhibition of Erythromycin and Erythromycin-Induced Resistance among Staphylococcus aureus Clinical Isolates
by Aya A. Mahfouz, Heba S. Said, Sherin M. Elfeky and Mona I. Shaaban
Antibiotics 2023, 12(3), 503; https://doi.org/10.3390/antibiotics12030503 - 02 Mar 2023
Cited by 4 | Viewed by 4875
Abstract
The increasing incidence of erythromycin and erythromycin-induced resistance to clindamycin among Staphylococcus aureus (S. aureus) is a serious problem. Patients infected with inducible resistance phenotypes may fail to respond to clindamycin. This study aimed to identify the prevalence of erythromycin and [...] Read more.
The increasing incidence of erythromycin and erythromycin-induced resistance to clindamycin among Staphylococcus aureus (S. aureus) is a serious problem. Patients infected with inducible resistance phenotypes may fail to respond to clindamycin. This study aimed to identify the prevalence of erythromycin and erythromycin-induced resistance and assess for potential inhibitors. A total of 99 isolates were purified from various clinical sources. Phenotypic detection of macrolide-lincosamide-streptogramin B (MLSB)-resistance phenotypes was performed by D-test. MLSB-resistance genes were identified using PCR. Different compounds were tested for their effects on erythromycin and inducible clindamycin resistance by broth microdilution and checkerboard microdilution methods. The obtained data were evaluated using docking analysis. Ninety-one isolates were S. aureus. The prevalence of constitutive MLSB, inducible MLSB, and macrolide-streptogramin (MS) phenotypes was 39.6%, 14.3%, and 2.2%, respectively. Genes including ermC, ermA, ermB, msrA, msrB, lnuA, and mphC were found in 82.6%, 5.8%, 7.7%, 3.8%, 3.8%, 13.5%, and 3.8% of isolates, respectively. Erythromycin resistance was significantly reduced by doxorubicin, neomycin, and omeprazole. Quinine, ketoprofen, and fosfomycin combated and reversed erythromycin/clindamycin-induced resistance. This study highlighted the significance of managing antibiotic resistance and overcoming clindamycin treatment failure. Doxorubicin, neomycin, omeprazole, quinine, ketoprofen, and fosfomycin could be potential inhibitors of erythromycin and inducible clindamycin resistance. Full article
(This article belongs to the Special Issue Antibacterial Resistance and Novel Therapeutic Strategies)
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14 pages, 2881 KiB  
Article
High Throughput Virtual Screening and Molecular Dynamics Simulation for Identifying a Putative Inhibitor of Bacterial CTX-M-15
by Shazi Shakil, Syed M. Danish Rizvi and Nigel H. Greig
Antibiotics 2021, 10(5), 474; https://doi.org/10.3390/antibiotics10050474 - 21 Apr 2021
Cited by 12 | Viewed by 3156
Abstract
Background: Multidrug resistant bacteria are a major therapeutic challenge. CTX-M-type enzymes are an important group of class A extended-spectrum β-lactamases (ESBLs). ESBLs are the enzymes that arm bacterial pathogens with drug resistance to an array of antibiotics, notably the advanced-generation cephalosporins. The current [...] Read more.
Background: Multidrug resistant bacteria are a major therapeutic challenge. CTX-M-type enzymes are an important group of class A extended-spectrum β-lactamases (ESBLs). ESBLs are the enzymes that arm bacterial pathogens with drug resistance to an array of antibiotics, notably the advanced-generation cephalosporins. The current need for an effective CTX-M-inhibitor is high. Objective: The aim of the current study was to identify a promising anti-CTX-M-15 ligand whose chemical skeleton could be used as a ‘seed-molecule’ for future drug design against resistant bacteria. Methods: Virtual screening of 5,000,000 test molecules was performed by ‘MCULE Drug Discovery Platform’. ‘ADME analyses’ was performed by ‘SWISS ADME’. TOXICITY CHECKER of MCULE was employed to predict the safety profile of the test molecules. The complex of the ‘Top inhibitor’ with the ‘bacterial CTX-M-15 enzyme’ was subjected to 102.25 ns molecular dynamics simulation. This simulation was run for 3 days on a HP ZR30w workstation. Trajectory analyses were performed by employing the macro ‘md_analyze.mcr’ of YASARA STRUCTURE version 20.12.24.W.64 using AMBER14 force field. YANACONDA macro language was used for complex tasks. Figures, including RMSD and RMSF plots, were generated. Snapshots were acquired after every 250 ps. Finally, two short videos of ‘41 s’ and ‘1 min and 22 s’ duration were recorded. Results: 5-Amino-1-(2H-[1,2,4]triazino[5,6-b]indol-3-yl)-1H-pyrazole-4-carbonitrile, denoted by the MCULE-1352214421-0-56, displayed the most efficient binding with bacterial CTX-M-15 enzyme. This screened molecule significantly interacted with CTX-M-15 via 13 amino acid residues. Notably, nine amino acid residues were found common to avibactam binding (the reference ligand). Trajectory analysis yielded 410 snapshots. The RMSD plot revealed that around 26 ns, equilibrium was achieved and, thereafter, the complex remained reasonably stable. After a duration of 26 ns and onwards until 102.25 ns, the backbone RMSD fluctuations were found to be confined within a range of 0.8–1.4 Å. Conclusion: 5-Amino-1-(2H-[1,2,4]triazino[5,6-b]indol-3-yl)-1H-pyrazole-4-carbonitrile could emerge as a promising seed molecule for CTX-M-15-inhibitor design. It satisfied ADMET features and displayed encouraging ‘simulation results’. Advanced plots obtained by trajectory analyses predicted the stability of the proposed protein-ligand complex. ‘Hands on’ wet laboratory validation is warranted. Full article
(This article belongs to the Special Issue Antibacterial Resistance and Novel Therapeutic Strategies)
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11 pages, 3772 KiB  
Article
Antimicrobial and Antibiofilm Properties of Graphene Oxide on Enterococcus faecalis
by Cecilia Martini, Francesca Longo, Raffaella Castagnola, Luca Marigo, Nicola Maria Grande, Massimo Cordaro, Margherita Cacaci, Massimiliano Papi, Valentina Palmieri, Francesca Bugli and Maurizio Sanguinetti
Antibiotics 2020, 9(10), 692; https://doi.org/10.3390/antibiotics9100692 - 13 Oct 2020
Cited by 14 | Viewed by 2435
Abstract
The aim of this study was to evaluate the antibacterial properties of graphene oxide (GO) against Enterococcus faecalis in vitro conditions and when used to coat dentin surface to prevent E. faecalis adhesion. The ATCC strain of E. faecalis 29212 has been used [...] Read more.
The aim of this study was to evaluate the antibacterial properties of graphene oxide (GO) against Enterococcus faecalis in vitro conditions and when used to coat dentin surface to prevent E. faecalis adhesion. The ATCC strain of E. faecalis 29212 has been used to perform a viability test. The pellet was suspended in ultrapure water, NaCl, PBS buffer, CaCl2 and MgCl2, Luria−Bertani broth solutions. The viability was evaluated by the colony forming unit counting method. Atomic force microscopy images and the measure of surface zeta potential variation were analyzed. Dentin discs were covered with a film of GO (n = 15) or were not treated (n = 15). Bacterial suspension was added to each sample of dentine discs and microbial counts were calculated. Statistically significant differences between two groups were assessed by a two-tailed unpaired t-test. Bacteria cell morphology was investigated with scanning electron microscopy. The highest growth inhibition was obtained in ddH2O and CaCl2 solution while, in PBS and NaCl, GO had poor antibacterial efficacy with a growth enhancing effect in the latter. GO on dentin discs demonstrated high antibacterial activity. GO film has demonstrated acceptable adhesion properties to root dentin and a role in the inhibition of bacterial film proliferation and biofilm formation. Full article
(This article belongs to the Special Issue Antibacterial Resistance and Novel Therapeutic Strategies)
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10 pages, 883 KiB  
Article
In Vitro Activities of Colistin and Sitafloxacin Combinations against Multidrug-, Carbapenem-, and Colistin-Resistant Acinetobacter baumannii Using the Broth Microdilution Checkerboard and Time-Kill Methods
by Vipavee Rodjun, Jantana Houngsaitong, Preecha Montakantikul, Taniya Paiboonvong, Piyatip Khuntayaporn, Pattareeya Yanyongchaikit and Pusana Sriyant
Antibiotics 2020, 9(8), 516; https://doi.org/10.3390/antibiotics9080516 - 14 Aug 2020
Cited by 6 | Viewed by 3709
Abstract
Drug-resistant Acinetobacter baumannii (A. baumannii) infections are a critical global problem, with limited treatment choices. This study aims to determine the in vitro activities of colistin–sitafloxacin combinations against multidrug-, carbapenem- and colistin-resistant A. baumannii (MDR-AB, CRAB, CoR-AB, respectively) clinical isolates from tertiary [...] Read more.
Drug-resistant Acinetobacter baumannii (A. baumannii) infections are a critical global problem, with limited treatment choices. This study aims to determine the in vitro activities of colistin–sitafloxacin combinations against multidrug-, carbapenem- and colistin-resistant A. baumannii (MDR-AB, CRAB, CoR-AB, respectively) clinical isolates from tertiary care hospitals. We used the broth microdilution checkerboard and time-kill methods in this study. Synergy was found using both methods. The colistin–sitafloxacin combination showed synergy in MDR-AB, CRAB, and CoR-AB isolates (3.4%, 3.1%, and 20.9%, respectively). No antagonism was found in any type of drug-resistant isolate. The majority of CoR-AB isolates became susceptible to colistin (95.4%). The time-kill method also showed that this combination could suppress regrowth back to the initial inocula of all representative isolates. Our results demonstrated that the colistin–sitafloxacin combination might be an interesting option for the treatment of drug-resistant A. baumannii. However, further in vivo and clinical studies are required. Full article
(This article belongs to the Special Issue Antibacterial Resistance and Novel Therapeutic Strategies)
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Review

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23 pages, 946 KiB  
Review
Bacterial Nosocomial Infections: Multidrug Resistance as a Trigger for the Development of Novel Antimicrobials
by Sílvia A. Sousa, Joana R. Feliciano, Tiago Pita, Catarina F. Soeiro, Beatriz L. Mendes, Luis G. Alves and Jorge H. Leitão
Antibiotics 2021, 10(8), 942; https://doi.org/10.3390/antibiotics10080942 - 04 Aug 2021
Cited by 8 | Viewed by 3388
Abstract
Nosocomial bacterial infections are associated with high morbidity and mortality, posing a huge burden to healthcare systems worldwide. The ongoing COVID-19 pandemic, with the raised hospitalization of patients and the increased use of antimicrobial agents, boosted the emergence of difficult-to-treat multidrug-resistant (MDR) bacteria [...] Read more.
Nosocomial bacterial infections are associated with high morbidity and mortality, posing a huge burden to healthcare systems worldwide. The ongoing COVID-19 pandemic, with the raised hospitalization of patients and the increased use of antimicrobial agents, boosted the emergence of difficult-to-treat multidrug-resistant (MDR) bacteria in hospital settings. Therefore, current available antibiotic treatments often have limited or no efficacy against nosocomial bacterial infections, and novel therapeutic approaches need to be considered. In this review, we analyze current antibacterial alternatives under investigation, focusing on metal-based complexes, antimicrobial peptides, and antisense antimicrobial therapeutics. The association of new compounds with older, commercially available antibiotics and the repurposing of existing drugs are also revised in this work. Full article
(This article belongs to the Special Issue Antibacterial Resistance and Novel Therapeutic Strategies)
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