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Antibiotics
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Efflux Pumps in Bacteria: What They Do and How We...
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Efflux Pumps in Bacteria: What They Do and How We Can Stop Them

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

Deadline for manuscript submissions: 15 September 2024 | Viewed by 17812

Special Issue Editor

Dr. Tommaso Felicetti

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Perugia, 06125 Perugia, Italy
Interests: medicinal chemistry; organic chemistry; chemical biology; antibiotics; antiviral agents; anticancer agents; efflux pump inhibitors; polymerase inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Antimicrobial resistance (AMR) represents a growing risk for our global health, jeopardizing our lifestyle and the world economy. Among different mechanisms by which AMR can develop, efflux pumps play a central role. Indeed, microbial efflux pumps can contribute to AMR by extruding noxious agents, such as antibacterials, from the cytoplasm, thus producing a reduction of the antibacterial effect. Accordingly, this decrease of antimicrobials inside the bacterial cells can promote the development of more specific mechanisms of resistance, such as target modification or antibiotic-modifying or -degrading enzymes. In addition, microbial efflux pumps have been identified as important players in the formation of biofilm as well as in the complex signaling mechanism called quorum sensing. Therefore, the identification of new non-antibiotic molecules able to block microbial efflux pumps represents a promising approach to fight AMR. Indeed, efflux pump inhibitors (EPIs) have the potential to synergize with common antibiotics that are efflux pump substrates, thus restoring their antibacterial effect. In addition, EPIs could reduce the development of resistance by i) preventing the first nonspecific extrusion of antibiotics, ii) reducing biofilm formation and iii) modulating quorum sensing.

This Special Issue aims to collect high-quality reviews and original papers aiming at enriching our knowledge about microbial efflux pumps, their role in the development of AMR, and strategies to block them by EPI molecules.

Dr. Tommaso Felicetti
Guest Editor

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

  • new antibiotics
  • bioactive medicinal agents
  • classes of antibiotics
  • antibiotic resistance and misuse
  • natural antibiotics
  • microbial efflux pumps
  • efflux pump inhibitors

Published Papers (6 papers)

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Research

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12 pages, 595 KiB  
Article
Inhibition of Staphylococcus pseudintermedius Efflux Pumps by Using Staphylococcus aureus NorA Efflux Pump Inhibitors
by Elisa Rampacci, Tommaso Felicetti, Giada Cernicchi, Valentina Stefanetti, Stefano Sabatini and Fabrizio Passamonti
Antibiotics 2023, 12(5), 806; https://doi.org/10.3390/antibiotics12050806 - 24 Apr 2023
Viewed by 1211
Abstract
One promising approach in treating antibiotic-resistant bacteria is to “break” resistances connected with antibacterial efflux by co-administering efflux pump inhibitors (EPIs) with antibiotics. Here, ten compounds, previously optimized to restore the susceptibility to ciprofloxacin (CIP) of norA-overexpressing Staphylococcus aureus, were evaluated [...] Read more.
One promising approach in treating antibiotic-resistant bacteria is to “break” resistances connected with antibacterial efflux by co-administering efflux pump inhibitors (EPIs) with antibiotics. Here, ten compounds, previously optimized to restore the susceptibility to ciprofloxacin (CIP) of norA-overexpressing Staphylococcus aureus, were evaluated for their ability to inhibit norA-mediated efflux in Staphylococcus pseudintermedius and synergize with CIP, ethidium bromide (EtBr), gentamycin (GEN), and chlorhexidine digluconate (CHX). We focused efforts on S. pseudintermedius as a pathogenic bacterium of concern within veterinary and human medicine. By combining data from checkerboard assays and EtBr efflux inhibition experiments, the hits 2-arylquinoline 1, dihydropyridine 6, and 2-phenyl-4-carboxy-quinoline 8 were considered the best EPIs for S. pseudintermedius. Overall, most of the compounds, except for 2-arylquinoline compound 2, were able to fully restore the susceptibility of S. pseudintermedius to CIP and synergize with GEN as well, while the synergistic effect with CHX was less significant and often did not show a dose-dependent effect. These are valuable data for medicinal chemistry optimization of EPIs for S. pseudintermedius and lay the foundation for further studies on successful EPIs to treat staphylococcal infections. Full article
(This article belongs to the Special Issue Efflux Pumps in Bacteria: What They Do and How We Can Stop Them)
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15 pages, 2268 KiB  
Article
Plant Secondary Metabolites on Efflux-Mediated Antibiotic Resistant Stenotrophomonas Maltophilia: Potential of Herbal-Derived Efflux Pump Inhibitors
by Thi Huyen Thu Nguyen, Ngoc Anh Thơ Nguyen, Hai Dang Nguyen, Thi Thu Hien Nguyen, Mai Huong Le, Minh Quan Pham, Huu Nghi Do, Kim Chi Hoang, Serge Michalet, Marie-Geneviève Dijoux-Franca and Hoang Nam Pham
Antibiotics 2023, 12(2), 421; https://doi.org/10.3390/antibiotics12020421 - 20 Feb 2023
Cited by 3 | Viewed by 1954
Abstract
During the process of adapting to metal contamination, plants produce secondary metabolites that have the potential to modulate multidrug-resistant (MDR) phenotypes; this is achieved by inhibiting the activity of efflux pumps to reduce the minimum inhibitory concentrations (MICs) of antimicrobial substrates. Our study [...] Read more.
During the process of adapting to metal contamination, plants produce secondary metabolites that have the potential to modulate multidrug-resistant (MDR) phenotypes; this is achieved by inhibiting the activity of efflux pumps to reduce the minimum inhibitory concentrations (MICs) of antimicrobial substrates. Our study evaluated the effect of secondary metabolites of belowground parts of Pteris vittata L. and Fallopia japonica, two metal-tolerant plants from northern Vietnam, on six antibiotic-resistant Stenotrophomonas maltophilia strains possessing efflux pump resistance mechanisms that were isolated from soil and clinical samples. The chemical composition of aqueous and dichloromethane (DCM) fractions extracted from P. vittata and F. japonica was determined using UHPLC-DAD-ESI/QTOF analysis. The antibacterial and efflux pump inhibitory activities of the four fractions were evaluated for the six strains (K279a, 0366, BurA1, BurE1, PierC1, and 502) using a microdilution assay at fraction concentrations of 62.5, 125, and 250 μg/mL. The DCM fraction of F. japonica exhibited remarkable antibacterial activity against strain 0366, with a MIC of 31.25 μg/mL. Furthermore, this fraction also significantly decreased gentamicin MIC: four-fold and eight-fold reductions for BurA1 and BurE1 strains, respectively (when tested at 250 μg/mL), and two-fold and eight-fold reductions for K279a and BurE1 strains, respectively (when tested at 125 μg/mL). Pure emodin, the main component identified in the DCM fraction of F. japonica, and sennidine A&B only reduced by half the MIC of gentamicin (when tested at 30 μg/mL). Our results suggest that the DCM fraction components of F. japonica underground parts may be potential candidates for new bacterial efflux pump inhibitors (EPIs). Full article
(This article belongs to the Special Issue Efflux Pumps in Bacteria: What They Do and How We Can Stop Them)
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Review

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35 pages, 2104 KiB  
Review
Antimicrobial Resistance: Two-Component Regulatory Systems and Multidrug Efflux Pumps
by Giuseppe Valerio De Gaetano, Germana Lentini, Agata Famà, Francesco Coppolino and Concetta Beninati
Antibiotics 2023, 12(6), 965; https://doi.org/10.3390/antibiotics12060965 - 26 May 2023
Cited by 10 | Viewed by 4073
Abstract
The number of multidrug-resistant bacteria is rapidly spreading worldwide. Among the various mechanisms determining resistance to antimicrobial agents, multidrug efflux pumps play a noteworthy role because they export extraneous and noxious substrates from the inside to the outside environment of the bacterial cell [...] Read more.
The number of multidrug-resistant bacteria is rapidly spreading worldwide. Among the various mechanisms determining resistance to antimicrobial agents, multidrug efflux pumps play a noteworthy role because they export extraneous and noxious substrates from the inside to the outside environment of the bacterial cell contributing to multidrug resistance (MDR) and, consequently, to the failure of anti-infective therapies. The expression of multidrug efflux pumps can be under the control of transcriptional regulators and two-component systems (TCS). TCS are a major mechanism by which microorganisms sense and reply to external and/or intramembrane stimuli by coordinating the expression of genes involved not only in pathogenic pathways but also in antibiotic resistance. In this review, we describe the influence of TCS on multidrug efflux pump expression and activity in some Gram-negative and Gram-positive bacteria. Taking into account the strict correlation between TCS and multidrug efflux pumps, the development of drugs targeting TCS, alone or together with already discovered efflux pump inhibitors, may represent a beneficial strategy to contribute to the fight against growing antibiotic resistance. Full article
(This article belongs to the Special Issue Efflux Pumps in Bacteria: What They Do and How We Can Stop Them)
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19 pages, 1019 KiB  
Review
Efflux, Signaling and Warfare in a Polymicrobial World
by Ay’sha Moore-Machacek, Antje Gloe, Niall O’Leary and F. Jerry Reen
Antibiotics 2023, 12(4), 731; https://doi.org/10.3390/antibiotics12040731 - 08 Apr 2023
Cited by 2 | Viewed by 1686
Abstract
The discovery void of antimicrobial development has occurred at a time when the world has seen a rapid emergence and spread of antimicrobial resistance, the ‘perfect storm’ as it has often been described. While the discovery and development of new antibiotics has continued [...] Read more.
The discovery void of antimicrobial development has occurred at a time when the world has seen a rapid emergence and spread of antimicrobial resistance, the ‘perfect storm’ as it has often been described. While the discovery and development of new antibiotics has continued in the research sphere, the pipeline to clinic has largely been fed by derivatives of existing classes of antibiotics, each prone to pre-existing resistance mechanisms. A novel approach to infection management has come from the ecological perspective whereby microbial networks and evolved communities already possess small molecular capabilities for pathogen control. The spatiotemporal nature of microbial interactions is such that mutualism and parasitism are often two ends of the same stick. Small molecule efflux inhibitors can directly target antibiotic efflux, a primary resistance mechanism adopted by many species of bacteria and fungi. However, a much broader anti-infective capability resides within the action of these inhibitors, borne from the role of efflux in key physiological and virulence processes, including biofilm formation, toxin efflux, and stress management. Understanding how these behaviors manifest within complex polymicrobial communities is key to unlocking the full potential of the advanced repertoires of efflux inhibitors. Full article
(This article belongs to the Special Issue Efflux Pumps in Bacteria: What They Do and How We Can Stop Them)
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33 pages, 17163 KiB  
Review
Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria
by Nina Compagne, Anais Vieira Da Cruz, Reinke T. Müller, Ruben C. Hartkoorn, Marion Flipo and Klaas M. Pos
Antibiotics 2023, 12(1), 180; https://doi.org/10.3390/antibiotics12010180 - 15 Jan 2023
Cited by 22 | Viewed by 4702
Abstract
Antimicrobial resistance (AMR) has become a major problem in public health leading to an estimated 4.95 million deaths in 2019. The selective pressure caused by the massive and repeated use of antibiotics has led to bacterial strains that are partially or even entirely [...] Read more.
Antimicrobial resistance (AMR) has become a major problem in public health leading to an estimated 4.95 million deaths in 2019. The selective pressure caused by the massive and repeated use of antibiotics has led to bacterial strains that are partially or even entirely resistant to known antibiotics. AMR is caused by several mechanisms, among which the (over)expression of multidrug efflux pumps plays a central role. Multidrug efflux pumps are transmembrane transporters, naturally expressed by Gram-negative bacteria, able to extrude and confer resistance to several classes of antibiotics. Targeting them would be an effective way to revive various options for treatment. Many efflux pump inhibitors (EPIs) have been described in the literature; however, none of them have entered clinical trials to date. This review presents eight families of EPIs active against Escherichia coli or Pseudomonas aeruginosa. Structure–activity relationships, chemical synthesis, in vitro and in vivo activities, and pharmacological properties are reported. Their binding sites and their mechanisms of action are also analyzed comparatively. Full article
(This article belongs to the Special Issue Efflux Pumps in Bacteria: What They Do and How We Can Stop Them)
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26 pages, 1346 KiB  
Review
What Approaches to Thwart Bacterial Efflux Pumps-Mediated Resistance?
by Armel Jackson Seukep, Helene Gueaba Mbuntcha, Victor Kuete, Yindi Chu, Enguo Fan and Ming-Quan Guo
Antibiotics 2022, 11(10), 1287; https://doi.org/10.3390/antibiotics11101287 - 21 Sep 2022
Cited by 12 | Viewed by 2991
Abstract
An effective response that combines prevention and treatment is still the most anticipated solution to the increasing incidence of antimicrobial resistance (AMR). As the phenomenon continues to evolve, AMR is driving an escalation of hard-to-treat infections and mortality rates. Over the years, bacteria [...] Read more.
An effective response that combines prevention and treatment is still the most anticipated solution to the increasing incidence of antimicrobial resistance (AMR). As the phenomenon continues to evolve, AMR is driving an escalation of hard-to-treat infections and mortality rates. Over the years, bacteria have devised a variety of survival tactics to outwit the antibiotic’s effects, yet given their great adaptability, unexpected mechanisms are still to be discovered. Over-expression of efflux pumps (EPs) constitutes the leading strategy of bacterial resistance, and it is also a primary driver in the establishment of multidrug resistance (MDR). Extensive efforts are being made to develop antibiotic resistance breakers (ARBs) with the ultimate goal of re-sensitizing bacteria to medications to which they have become unresponsive. EP inhibitors (EPIs) appear to be the principal group of ARBs used to impair the efflux system machinery. Due to the high toxicity of synthetic EPIs, there is a growing interest in natural, safe, and innocuous ones, whereby plant extracts emerge to be excellent candidates. Besides EPIs, further alternatives are being explored including the development of nanoparticle carriers, biologics, and phage therapy, among others. What roles do EPs play in the occurrence of MDR? What weapons do we have to thwart EP-mediated resistance? What are the obstacles to their development? These are some of the core questions addressed in the present review. Full article
(This article belongs to the Special Issue Efflux Pumps in Bacteria: What They Do and How We Can Stop Them)
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