Beating the Bugs: Alternative Approaches to Reverse Antibiotic Resistance in Infectious Bacterial Pathogens

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Mechanism and Evolution of Antibiotic Resistance".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 13499

Special Issue Editors


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Guest Editor
Mycobacteria Research Laboratory, Department of Biological Science, Institute of Structural and Molecular Biology, Birkbeck, University of London/UCL, Malet Street, London WC1E 7HX , UK
Interests: tuberculosis; antimicrobial drug resistance; target validation; new drug discovery; repurposing drugs
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Guest Editor
Birkbeck, University of London, London, UK
Interests: Mycobacterium tuberculosis; antimicrobial resistance; drug discovery; validation of novel therapeutic targets; repurposing drugs

Special Issue Information

Dear Colleagues,

We are 30 years away from the dire prediction that antimicrobial resistance (AMR) will claim 10 million lives a year and cost the world 100 trillion USD. Over the last decade, industry and academia have collaborated and mobilised forces in preparation to avert this public health crisis however, these efforts are yet to have an effect on the global AMR trends. Currently, infections caused by ‘superbugs’ claim the lives of an estimated 700,000 worldwide. A large majority of these infections in caused by strains of Mycobacterium tuberculosis and the ESKAPE group of infectious bacterial pathogens comprising of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and the Enterobacter species. Transmission of resistance and increasing resistance profiles of these organisms make their control and treatment extremely challenging in the current environment of limited drug options that are still effective against them.

With calls urging our attention towards tackling the post-antibiotic era, research and development has to stay ahead and at times pre-empt the evolution of these pathogens. It is time to diversify our approach by attacking the instrinsic mechanisms of drug resistance such as efflux pumps, formation of biofilms and the activity of drug modifying enzymes to name a few. Therefore, instead of the conventional route of targeting novel pathways wherein resistance is quick to develop, these approaches will serve to reverse resistance and potentiate currently available therapy.

In this Special Issue, we aim to highlight the importance of interdisciplinary approaches in accelerating new drug development and repurposing existing drugs.

We invite authors to send in their manuscripts in the areas of interest as highlighted below:

  • Importance of rational drug design vis-a-vis whole-cell evaluation of chemical libraries
  • Reversing resistance by affecting intrinsic mechanisms of resistance
    • β-lactamase inhibition
    • Efflux pump inhibition
    • Disruption of biofilm
    • Membrane permeabilisers
    • Development of drug carriers that increase uptake of antibiotics
  • Alternative therapeutic routes
    • Phage therapy
    • Therapeutic vaccine development

Manuscripts that further our understanding of antimicrobial resistance, means to reverse them, and novel approaches not in this list specifically, yet still falling within the scope of the Special Issue are also welcome.

Prof. Sanjib Bhakta
Dr. Arundhati Maitra
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

  • Mycobacterium tuberculosis
  • Antimicrobial resistance
  • Drug discovery
  • Validation of novel therapeutic targets
  • Repurposing drugs

Published Papers (3 papers)

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Research

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17 pages, 3423 KiB  
Article
Potential Target Site for Inhibitors in MLSB Antibiotic Resistance
by Hak Jin Lee, Seong Tae Jhang and Hyung Jong Jin
Antibiotics 2021, 10(3), 264; https://doi.org/10.3390/antibiotics10030264 - 5 Mar 2021
Cited by 2 | Viewed by 2448
Abstract
Macrolide–lincosamide–streptogramin B antibiotic resistance occurs through the action of erythromycin ribosome methylation (Erm) family proteins, causing problems due to their prevalence and high minimal inhibitory concentration, and feasibilities have been sought to develop inhibitors. Erms exhibit high conservation next to the N-terminal end [...] Read more.
Macrolide–lincosamide–streptogramin B antibiotic resistance occurs through the action of erythromycin ribosome methylation (Erm) family proteins, causing problems due to their prevalence and high minimal inhibitory concentration, and feasibilities have been sought to develop inhibitors. Erms exhibit high conservation next to the N-terminal end region (NTER) as in ErmS, 64SQNF67. Side chains of homologous S, Q and F in ErmC’ are surface-exposed, located closely together and exhibit intrinsic flexibility; these residues form a motif X. In S64 mutations, S64G, S64A and S64C exhibited 71%, 21% and 20% activity compared to the wild-type, respectively, conferring cell resistance. However, mutants harboring larger side chains did not confer resistance and retain the methylation activity in vitro. All mutants of Q65, Q65N, Q65E, Q65R, and Q65H lost their methyl group transferring activity in vivo and in vitro. At position F67, a size reduction of side-chain (F67A) or a positive charge (F67H) greatly reduced the activity to about 4% whereas F67L with a small size reduction caused a moderate loss, more than half of the activity. The increased size by F67Y and F67W reduced the activity by about 75%. In addition to stabilization of the cofactor, these amino acids could interact with substrate RNA near the methylatable adenine presumably to be catalytically well oriented with the SAM (S-adenosyl-L-methionine). These amino acids together with the NTER beside them could serve as unique potential inhibitor development sites. This region constitutes a divergent element due to the NTER which has variable length and distinct amino acids context in each Erm. The NTER or part of it plays critical roles in selective recognition of substrate RNA by Erms and this presumed target site might assume distinct local structure by induced conformational change with binding to substrate RNA and SAM, and contribute to the specific recognition of substrate RNA. Full article
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16 pages, 3963 KiB  
Article
Weighted Gene Co-Expression Network Analysis Identifies Key Modules and Hub Genes Associated with Mycobacterial Infection of Human Macrophages
by Lu Lu, RanLei Wei, Sanjib Bhakta, Simon J. Waddell and Ester Boix
Antibiotics 2021, 10(2), 97; https://doi.org/10.3390/antibiotics10020097 - 20 Jan 2021
Cited by 6 | Viewed by 3118 | Correction
Abstract
Tuberculosis (TB) is still a leading cause of death worldwide. Treatments remain unsatisfactory due to an incomplete understanding of the underlying host–pathogen interactions during infection. In the present study, weighted gene co-expression network analysis (WGCNA) was conducted to identify key macrophage modules and [...] Read more.
Tuberculosis (TB) is still a leading cause of death worldwide. Treatments remain unsatisfactory due to an incomplete understanding of the underlying host–pathogen interactions during infection. In the present study, weighted gene co-expression network analysis (WGCNA) was conducted to identify key macrophage modules and hub genes associated with mycobacterial infection. WGCNA was performed combining our own transcriptomic results using Mycobacterium aurum-infected human monocytic macrophages (THP1) with publicly accessible datasets obtained from three types of macrophages infected with seven different mycobacterial strains in various one-to-one combinations. A hierarchical clustering tree of 11,533 genes was built from 198 samples, and 47 distinct modules were revealed. We identified a module, consisting of 226 genes, which represented the common response of host macrophages to different mycobacterial infections that showed significant enrichment in innate immune stimulation, bacterial pattern recognition, and leukocyte chemotaxis. Moreover, by network analysis applied to the 74 genes with the best correlation with mycobacteria infection, we identified the top 10 hub-connecting genes: NAMPT, IRAK2, SOCS3, PTGS2, CCL20, IL1B, ZC3H12A, ABTB2, GFPT2, and ELOVL7. Interestingly, apart from the well-known Toll-like receptor and inflammation-associated genes, other genes may serve as novel TB diagnosis markers and potential therapeutic targets. Full article
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Review

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17 pages, 3147 KiB  
Review
Pharmacokinetics of Non-β-Lactam β-Lactamase Inhibitors
by Giacomo Luci, Francesca Mattioli, Marco Falcone and Antonello Di Paolo
Antibiotics 2021, 10(7), 769; https://doi.org/10.3390/antibiotics10070769 - 24 Jun 2021
Cited by 12 | Viewed by 6310
Abstract
The growing emergence of drug-resistant bacterial strains is an issue to treat severe infections, and many efforts have identified new pharmacological agents. The inhibitors of β-lactamases (BLI) have gained a prominent role in the safeguard of beta-lactams. In the last years, new β-lactam–BLI [...] Read more.
The growing emergence of drug-resistant bacterial strains is an issue to treat severe infections, and many efforts have identified new pharmacological agents. The inhibitors of β-lactamases (BLI) have gained a prominent role in the safeguard of beta-lactams. In the last years, new β-lactam–BLI combinations have been registered or are still under clinical evaluation, demonstrating their effectiveness to treat complicated infections. It is also noteworthy that the pharmacokinetics of BLIs partly matches that of β-lactams companions, meaning that some clinical situations, as well as renal impairment and renal replacement therapies, may alter the disposition of both drugs. Common pharmacokinetic characteristics, linear pharmacokinetics across a wide range of doses, and known pharmacokinetic/pharmacodynamic parameters may guide modifications of dosing regimens for both β-lactams and BLIs. However, comorbidities (i.e., burns, diabetes, cancer) and severe changes in individual pathological conditions (i.e., acute renal impairment, sepsis) could make dose adaptation difficult, because the impact of those factors on BLI pharmacokinetics is partly known. Therapeutic drug monitoring protocols may overcome those issues and offer strategies to personalize drug doses in the intensive care setting. Further prospective clinical trials are warranted to improve the use of BLIs and their β-lactam companions in severe and complicated infections. Full article
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