Antimicrobial Resistance and Drug Design—a Themed Issue in Honor of Professor Kim Lewis

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Novel Antimicrobial Agents".

Deadline for manuscript submissions: 29 February 2024 | Viewed by 12741

Special Issue Editor

Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
Interests: antibiotic resistance and discovery; multidrug efflux; drug permeation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue will honor Prof. Kim Lewis for his outstanding contributions in the fields of bacterial physiology, antibiotic discovery, and mechanisms of antibiotic resistance. Dr. Lewis is the University Distinguished Professor and the Director of the Antimicrobial Discovery Center at the Northeastern University in Boston, MA. Dr. Lewis is also a Fellow of the American Society for Microbiology and the American Association for the Advancement of Science (AAAS), and a member of the Faculty 1000 Pharmacology & Drug Discovery section.

Dr. Lewis is a graduate of Moscow University, USSR (M.S., Ph.D.) and completed a brief postdoctoral work at the University of Wisconsin, Madison. In 1988, he accepted his first faculty position as an Assistant Professor at the Department of Biology of the Massachusetts Institute of Technology (MIT) in Boston. During his time at MIT, Dr. Lewis made a ground-breaking discovery of the first ever bacterial efflux pump, the Escherichia coli EmrAB. Curiously, this discovery was made while he was looking for the mechanism of electron coupling in the respiratory chain using proton uncouplers, a bioenergetics interest from his graduate studies in Prof. Vladimir Skulachev’s lab. The increasing concentrations of the uncoupler CCCP led to the selection of resistant mutants that overproduced EmrAB responsible for the active efflux of this compound across the outer membrane. In 2001, Dr. Lewis has joined the Department of Biology at Northeastern University in Boston as Full Professor where he developed an interdisciplinary and highly recognized program on antibiotic resistance and discovery. The Discovery of new antibiotics is a difficult task, because screening for antibiotics from soil actinomycetes (the major producers of several clinical antibiotics) eventually became redundant with the same active chemotypes rediscovered multiple times, and because bacteria always find a way to resist antibiotics. Dr. Lewis found solutions to these hurdles and discovered novel antibiotics, for which selection of resistance is not easily achievable. He developed a technology to grow uncultured bacteria, which constitute 99% of all microbial diversity and tapped the diversity of their secondary metabolisms to discover teixobactin, lassomycin and darobactin, the antibiotics with new mechanisms of action. Dr. Lewis’s interest in the recalcitrance of chronic infections with biofilms to antibiotic treatments led to the rediscovery of persisters and characterization of the principal mechanism of persister formation and the role of persisters in the tolerance of biofilms to antibiotics.

Dr. Lewis’s current research interest, in his own words, is in the “mining of natural antimicrobiome to discover a perfect antibiotic, if it exists”. He has published more than 270 scientific papers with 46000+ citations. Dr. Lewis’s work is recognized by multiple awards, and he was recently selected as the 2023 ASM recipient of the Applied Biology and Biotechnology Research Award. He continues to push the frontier of bacteriology and because of his extraordinary efforts “where the frontier of science once was, is now the centre” (Georg Christoph Lichtenberg). I am honored and pleased to invite you to submit a publication for this Special Issue.

Prof. Dr. Helen I. Zgurskaya
Guest Editor

Manuscript Submission Information

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Keywords

  • antibiotics
  • mechanism of action
  • persisters
  • biofilms
  • uncultured bacteria
  • antibiotic resistance
  • multidrug efflux

Published Papers (6 papers)

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Research

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16 pages, 1880 KiB  
Article
Acinetobacter baumannii Survival under Infection-Associated Stresses Depends on the Expression of Resistance–Nodulation–Division and Major Facilitator Superfamily Efflux Pumps
Antibiotics 2024, 13(1), 7; https://doi.org/10.3390/antibiotics13010007 - 20 Dec 2023
Viewed by 2018
Abstract
Multidrug efflux transporters are major contributors to the antibiotic resistance of Acinetobacter baumannii in clinical settings. Previous studies showed that these transporters are tightly integrated into the physiology of A. baumannii and have diverse functions. However, for many of the efflux pumps, such [...] Read more.
Multidrug efflux transporters are major contributors to the antibiotic resistance of Acinetobacter baumannii in clinical settings. Previous studies showed that these transporters are tightly integrated into the physiology of A. baumannii and have diverse functions. However, for many of the efflux pumps, such functions remain poorly defined. In this study, we characterized two putative drug efflux pumps, AmfAB and AmfCD (Acinetobacter Major Facilitator), that are homologous to EmrAB-like transporters from Escherichia coli and other Gram-negative bacteria. These pumps comprise the Major Facilitator Superfamily (MFS) transporters AmfB and AmfD and the periplasmic membrane fusion proteins AmfA and AmfC, respectively. We inactivated and overproduced these pumps in the wild-type ATCC 17978 strain and its derivative strains lacking the major efflux pumps from the Resistance–Nodulation–Division (RND) superfamily and characterized antibiotic susceptibilities and growth of the strains under stresses typical during human infections. We found that neither AmfAB nor AmfCD contribute to the antibiotic non-susceptibility phenotypes of A. baumannii. The two pumps, however, are critical for the adaptation and growth of the bacterium under acidic stress, whereas AmfCD also contributes to growth under conditions of low iron, high temperature, and in the presence of bile salts. These functions are dependent on the presence of the RND pumps, the inactivation of which further diminishes A. baumannii survival and growth. Our results suggest that MFS transporters contribute to stress survival by affecting the permeability properties of the A. baumannii cell envelope. Full article
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14 pages, 2306 KiB  
Article
Tamarindus indica Extract as a Promising Antimicrobial and Antivirulence Therapy
Antibiotics 2023, 12(3), 464; https://doi.org/10.3390/antibiotics12030464 - 24 Feb 2023
Cited by 2 | Viewed by 1925
Abstract
The worldwide crises from multi-drug-resistant (MDR) bacterial infections are pushing us to search for new alternative therapies. The renewed interest in medicinal plants has gained the attention of our research group. Tamarindus indica L. (T. indica) is one of the traditional [...] Read more.
The worldwide crises from multi-drug-resistant (MDR) bacterial infections are pushing us to search for new alternative therapies. The renewed interest in medicinal plants has gained the attention of our research group. Tamarindus indica L. (T. indica) is one of the traditional medicines used for a wide range of diseases. Therefore, we evaluated the antimicrobial activities of ethanolic extract of T. indica. The inhibitions zones, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and fractional inhibitor concentration indices (FICI) against Gram+ve and −ve pathogens were detected. The bioactive compounds from T. indica extract were identified by mass spectroscopy, thin-layer chromatography, and bio-autographic assay. We performed scanning electron microscopy (SEM) and molecular docking studies to confirm possible mechanisms of actions and antivirulence activities, respectively. We found more promising antimicrobial activities against MDR pathogens with MIC and MBC values for Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), i.e., (0.78, 3.12 mg/mL) and (1.56, 3.12 mg/mL), respectively. The antimicrobial activities of this extract were attributed to its capability to impair cell membrane permeability, inducing bacterial cell lysis, which was confirmed by the morphological changes observed under SEM. The synergistic interactions between this extract and commonly used antibiotics were confirmed (FICI values < 0.5). The bioactive compounds of this extract were bis (2-ethylhexyl)phthalate, phenol, 2,4-bis(1,1-dimethylethyl), 1,2-benzenedicarboxylic acid, and bis(8-methylnonyl) ester. Additionally, this extract showed antivirulence activities, especially against the S. aureus protease and P. aeruginosa elastase. In conclusion, we hope that pharmaceutical companies can utilize our findings to produce a new formulation of T. indica ethanolic extract with other antibiotics. Full article
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14 pages, 4525 KiB  
Article
Diversity and Distribution of β-Lactamase Genes Circulating in Indian Isolates of Multidrug-Resistant Klebsiella pneumoniae
Antibiotics 2023, 12(3), 449; https://doi.org/10.3390/antibiotics12030449 - 23 Feb 2023
Cited by 2 | Viewed by 2245
Abstract
Klebsiella pneumoniae (Kp) has gained prominence in the last two decades due to its global spread as a multidrug-resistant (MDR) pathogen. Further, carbapenem-resistant Kp are emerging at an alarming rate. The objective of this study was (1) to evaluate the prevalence of β [...] Read more.
Klebsiella pneumoniae (Kp) has gained prominence in the last two decades due to its global spread as a multidrug-resistant (MDR) pathogen. Further, carbapenem-resistant Kp are emerging at an alarming rate. The objective of this study was (1) to evaluate the prevalence of β-lactamases, especially carbapenemases, in Kp isolates from India, and (2) determine the most prevalent sequence type (ST) and plasmids, and their association with β-lactamases. Clinical samples of K. pneumoniae (n = 65) were collected from various pathology labs, and drug susceptibility and minimum inhibitory concentrations (MIC) were detected. Whole genome sequencing (WGS) was performed for n = 22 resistant isolates, including multidrug-resistant (MDR) (n = 4), extensively drug-resistant (XDR) (n = 15), and pandrug-resistant (PDR) (n = 3) categories, and genomic analysis was performed using various bioinformatics tools. Additional Indian MDRKp genomes (n = 187) were retrieved using the Pathosystems Resource Integration Center (PATRIC) database. Detection of β-lactamase genes, location (on chromosome or plasmid), plasmid replicons, and ST of genomes was carried out using CARD, mlplasmids, PlasmidFinder, and PubMLST, respectively. All data were analyzed and summarized using the iTOL tool. ST231 was highest, followed by ST147, ST2096, and ST14, among Indian isolates. blaampH was detected as the most prevalent gene, followed by blaCTX-M-15 and blaTEM-1. Among carbapenemase genes, blaOXA-232 was prevalent and associated with ST231, ST2096, and ST14, which was followed by blaNDM-5, which was observed to be prevalent in ST147, ST395, and ST437. ST231 genomes were most commonly found to carry Col440I and ColKP3 plasmids. ST16 carried mainly ColKP3, and Col(BS512) was abundantly present in ST147 genomes. One Kp isolate with a novel MLST profile was identified, which carried blaCTX-M-15, blaOXA-1, and blaTEM-1. ST16 and ST14 are mostly dual-producers of carbapenem and ESBL genes and could be emerging high-risk clones in India. Full article
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Review

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20 pages, 3251 KiB  
Review
Returning to Nature for the Next Generation of Antimicrobial Therapeutics
Antibiotics 2023, 12(8), 1267; https://doi.org/10.3390/antibiotics12081267 - 01 Aug 2023
Cited by 3 | Viewed by 1508
Abstract
Antibiotics found in and inspired by nature are life-saving cures for bacterial infections and have enabled modern medicine. However, the rise in resistance necessitates the discovery and development of novel antibiotics and alternative treatment strategies to prevent the return to a pre-antibiotic era. [...] Read more.
Antibiotics found in and inspired by nature are life-saving cures for bacterial infections and have enabled modern medicine. However, the rise in resistance necessitates the discovery and development of novel antibiotics and alternative treatment strategies to prevent the return to a pre-antibiotic era. Once again, nature can serve as a source for new therapies in the form of natural product antibiotics and microbiota-based therapies. Screening of soil bacteria, particularly actinomycetes, identified most of the antibiotics used in the clinic today, but the rediscovery of existing molecules prompted a shift away from natural product discovery. Next-generation sequencing technologies and bioinformatics advances have revealed the untapped metabolic potential harbored within the genomes of environmental microbes. In this review, we first highlight current strategies for mining this untapped chemical space, including approaches to activate silent biosynthetic gene clusters and in situ culturing methods. Next, we describe how using live microbes in microbiota-based therapies can simultaneously leverage many of the diverse antimicrobial mechanisms found in nature to treat disease and the impressive efficacy of fecal microbiome transplantation and bacterial consortia on infection. Nature-provided antibiotics are some of the most important drugs in human history, and new technologies and approaches show that nature will continue to offer valuable inspiration for the next generation of antibacterial therapeutics. Full article
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18 pages, 2131 KiB  
Review
An Update Review of Approaches to Multiple Action-Based Antibacterials
Antibiotics 2023, 12(5), 865; https://doi.org/10.3390/antibiotics12050865 - 06 May 2023
Cited by 3 | Viewed by 1526
Abstract
Many approaches are being pursued to address the major global health challenge posed by the increasing resistance of pathogenic bacteria to antibacterial agents. One of the promising approaches being investigated includes the design and development of multiple action-based small-molecule antibacterials. Aspects of this [...] Read more.
Many approaches are being pursued to address the major global health challenge posed by the increasing resistance of pathogenic bacteria to antibacterial agents. One of the promising approaches being investigated includes the design and development of multiple action-based small-molecule antibacterials. Aspects of this broad area have been reviewed previously, and recent developments are addressed in this update review covering the literature mainly over the past three years. Considerations encompassing drug combinations, single-molecule hybrids and prodrugs are summarised in regard to the intentional design and development of multiple-action agents with a focus on potential triple or greater activities in bacteria. The hope for such single agents or combinations of single agents is that resistance development will be significantly hindered, and they may be useful in tackling bacterial disease caused by both resistant and non-resistant bacteria. Full article
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20 pages, 1531 KiB  
Review
Targeting BAM for Novel Therapeutics against Pathogenic Gram-Negative Bacteria
Antibiotics 2023, 12(4), 679; https://doi.org/10.3390/antibiotics12040679 - 30 Mar 2023
Cited by 4 | Viewed by 2605
Abstract
The growing emergence of multidrug resistance in bacterial pathogens is an immediate threat to human health worldwide. Unfortunately, there has not been a matching increase in the discovery of new antibiotics to combat this alarming trend. Novel contemporary approaches aimed at antibiotic discovery [...] Read more.
The growing emergence of multidrug resistance in bacterial pathogens is an immediate threat to human health worldwide. Unfortunately, there has not been a matching increase in the discovery of new antibiotics to combat this alarming trend. Novel contemporary approaches aimed at antibiotic discovery against Gram-negative bacterial pathogens have expanded focus to also include essential surface-exposed receptors and protein complexes, which have classically been targeted for vaccine development. One surface-exposed protein complex that has gained recent attention is the β-barrel assembly machinery (BAM), which is conserved and essential across all Gram-negative bacteria. BAM is responsible for the biogenesis of β-barrel outer membrane proteins (β-OMPs) into the outer membrane. These β-OMPs serve essential roles for the cell including nutrient uptake, signaling, and adhesion, but can also serve as virulence factors mediating pathogenesis. The mechanism for how BAM mediates β-OMP biogenesis is known to be dynamic and complex, offering multiple modes for inhibition by small molecules and targeting by larger biologics. In this review, we introduce BAM and establish why it is a promising and exciting new therapeutic target and present recent studies reporting novel compounds and vaccines targeting BAM across various bacteria. These reports have fueled ongoing and future research on BAM and have boosted interest in BAM for its therapeutic promise in combatting multidrug resistance in Gram-negative bacterial pathogens. Full article
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