Special Issue "The Structural and Functional Study of Efflux Pumps Belonging to the RND Transporters Family from Gram-Negative Bacteria"

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: 30 November 2021.

Special Issue Editors

Dr. Isabelle Broutin
E-Mail Website
Guest Editor
Faculty of Pharmacy, Université de Paris, CNRS, laboratory CiTCoM
Interests: efflux pumps;structure;antibiotic resistance;membrane proteins
Prof. Attilio V Vargiu
E-Mail Website
Guest Editor
Physics, University of Cagliari, Cagliari, Italy
Interests: efflux pumps;molecular dynamics;enhanced-sampling methods;molecular docking;hydrogels
Prof. Dr. Henrietta Venter
E-Mail Website
Guest Editor
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
Interests: antimicrobial resistance; drug efflux proteins; novel antibiotics; mechanisms of resistance; multidrug resistance
Special Issues and Collections in MDPI journals
Dr. Gilles Phan
E-Mail Website
Guest Editor
Université de Paris, CNRS, laboratory CiTCoM
Interests: bacterial efflux pumps; secretion systems; two-components systems

Special Issue Information

Dear Colleagues,

Antimicrobial-resistant bacterial infections are a major and costly public health concern. Several pathogens are already pan-resistant, representing a major cause of mortality in patients suffering from nosocomial infections. Drug efflux pumps, which remove compounds from the bacterial cell, thereby lowering antimicrobial concentration to subtoxic levels, play a major role in multidrug resistance.

Gram-negative bacteria are particularly resistant, and some are identified by the World Health Organization as the most urgent priority of pathogens in need of new antimicrobial drug discovery. The clinically most relevant efflux pumps in Gram-negative bacteria belong to the RND (resistance nodulation cell division) family that forms a tripartite macromolecular assembly spanning both membranes and the periplasmic space of Gram-negative organisms. Along with functional studies and in silico approaches, many structures of the individual components, as well as that of the fully assembled pumps from several pathogens, have been solved. Nevertheless, a lot of questions concerning the assembly and the mechanism of efflux remain, and there are still no inhibitors of efflux pumps available in clinical treatment. 

In this Special Issue, we would like to present up-to-date knowledge of the mechanism of these efflux pumps, the identification and characterization of RND efflux pumps from emerging pathogens and their role in antimicrobial resistance, as well as progress made on the development of specific inhibitors (including the development of in vitro or in vivo tools for inhibitor selection). This collection of data could serve as a basis for antimicrobial drug discovery aimed at inhibiting drug efflux pumps to reverse resistance in some of the most resistant pathogens.

Dr. Isabelle Broutin
Prof. Attilio V Vargiu
Prof. Dr. Henrietta Venter
Dr. Gilles Phan
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 papers will be 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 1800 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

  • Antimicrobial resistance
  • RND transporters
  • Drug transport
  • Efflux pump
  • Structural biology
  • Molecular dynamics
  • Liposome
  • In cellulo measurement
  • Efflux pump inhibitor

Published Papers (5 papers)

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Research

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Article
Insight into the AcrAB-TolC Complex Assembly Process Learned from Competition Studies
Antibiotics 2021, 10(7), 830; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10070830 - 08 Jul 2021
Viewed by 505
Abstract
The RND family efflux pump AcrAB-TolC in E. coli and its homologs in other Gram-negative bacteria are major players in conferring multidrug resistance to the cells. While the structure of the pump complex has been elucidated with ever-increasing resolution through crystallography and Cryo-EM [...] Read more.
The RND family efflux pump AcrAB-TolC in E. coli and its homologs in other Gram-negative bacteria are major players in conferring multidrug resistance to the cells. While the structure of the pump complex has been elucidated with ever-increasing resolution through crystallography and Cryo-EM efforts, the dynamic assembly process remains poorly understood. Here, we tested the effect of overexpressing functionally defective pump components in wild type E. coli cells to probe the pump assembly process. Incorporation of a defective component is expected to reduce the efflux efficiency of the complex, leading to the so called “dominant negative” effect. Being one of the most intensively studied bacterial multidrug efflux pumps, many AcrA and AcrB mutations have been reported that disrupt efflux through different mechanisms. We examined five groups of AcrB and AcrA mutants, defective in different aspects of assembly and substrate efflux. We found that none of them demonstrated the expected dominant negative effect, even when expressed at concentrations many folds higher than their genomic counterpart. The assembly of the AcrAB-TolC complex appears to have a proof-read mechanism that effectively eliminated the formation of futile pump complex. Full article
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Article
RND Efflux Systems Contribute to Resistance and Virulence of Aliarcobacter butzleri
Antibiotics 2021, 10(7), 823; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10070823 - 06 Jul 2021
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Abstract
Aliarcobacter butzleri is an emergent enteropathogen that can be found in a range of environments. This bacterium presents a vast repertoire of efflux pumps, such as the ones belonging to the resistance nodulation cell division family, which may be associated with bacterial resistance, [...] Read more.
Aliarcobacter butzleri is an emergent enteropathogen that can be found in a range of environments. This bacterium presents a vast repertoire of efflux pumps, such as the ones belonging to the resistance nodulation cell division family, which may be associated with bacterial resistance, as well as virulence. Thus, this work aimed to evaluate the contribution of three RND efflux systems, AreABC, AreDEF and AreGHI, in the resistance and virulence of A. butzleri. Mutant strains were constructed by inactivation of the gene that encodes the inner membrane protein of these systems. The bacterial resistance profile of parental and mutant strains to several antimicrobials was assessed, as was the intracellular accumulation of the ethidium bromide dye. Regarding bacterial virulence, the role of these three efflux pumps on growth, strain fitness, motility, biofilm formation ability, survival in adverse conditions (oxidative stress and bile salts) and human serum and in vitro adhesion and invasion to Caco-2 cells was evaluated. We observed that the mutants from the three efflux pumps were more susceptible to several classes of antimicrobials than the parental strain and presented an increase in the accumulation of ethidium bromide, indicating a potential role of the efflux pumps in the extrusion of antimicrobials. The mutant strains had no bacterial growth defects; nonetheless, they presented a reduction in relative fitness. For the three mutants, an increase in the susceptibility to oxidative stress was observed, while only the mutant for AreGHI efflux pump showed a relevant role in bile stress survival. All the mutant strains showed an impairment in biofilm formation ability, were more susceptible to human serum and were less adherent to intestinal epithelial cells. Overall, the results support the contribution of the efflux pumps AreABC, AreDEF and AreGHI of A. butzleri to antimicrobial resistance, as well as to bacterial virulence. Full article
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Communication
Exploring the Contribution of the AcrB Homolog MdtF to Drug Resistance and Dye Efflux in a Multidrug Resistant E. coli Isolate
Antibiotics 2021, 10(5), 503; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10050503 - 28 Apr 2021
Viewed by 420
Abstract
In Escherichia coli, the role of RND-type drug transporters other than the major efflux pump AcrB has largely remained undeciphered (particularly in multidrug resistant pathogens), because genetic engineering in such isolates is challenging. The present study aimed to explore the capability of [...] Read more.
In Escherichia coli, the role of RND-type drug transporters other than the major efflux pump AcrB has largely remained undeciphered (particularly in multidrug resistant pathogens), because genetic engineering in such isolates is challenging. The present study aimed to explore the capability of the AcrB homolog MdtF to contribute to the extrusion of noxious compounds and to multidrug resistance in an E. coli clinical isolate with demonstrated expression of this efflux pump. An mdtF/acrB double-knockout was engineered, and susceptibility changes with drugs from various classes were determined in comparison to the parental strain and its acrB and tolC single-knockout mutants. The potential of MdtF to participate in the export of agents with different physicochemical properties was additionally assessed using accumulation and real-time efflux assays with several fluorescent dyes. The results show that there was limited impact to the multidrug resistant phenotype in the tested E. coli strain, while the RND-type transporter remarkably contributes to the efflux of all tested dyes. This should be considered when evaluating the efflux phenotype of clinical isolates via dye accumulation assays. Furthermore, the promiscuity of MdtF should be taken into account when developing new antibiotic agents. Full article
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Review

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Review
Role of RND Efflux Pumps in Drug Resistance of Cystic Fibrosis Pathogens
Antibiotics 2021, 10(7), 863; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10070863 - 15 Jul 2021
Viewed by 355
Abstract
Drug resistance represents a great concern among people with cystic fibrosis (CF), due to the recurrent and prolonged antibiotic therapy they should often undergo. Among Multi Drug Resistance (MDR) determinants, Resistance-Nodulation-cell Division (RND) efflux pumps have been reported as the main contributors, due [...] Read more.
Drug resistance represents a great concern among people with cystic fibrosis (CF), due to the recurrent and prolonged antibiotic therapy they should often undergo. Among Multi Drug Resistance (MDR) determinants, Resistance-Nodulation-cell Division (RND) efflux pumps have been reported as the main contributors, due to their ability to extrude a wide variety of molecules out of the bacterial cell. In this review, we summarize the principal RND efflux pump families described in CF pathogens, focusing on the main Gram-negative bacterial species (Pseudomonas aeruginosa, Burkholderia cenocepacia, Achromobacter xylosoxidans, Stenotrophomonas maltophilia) for which a predominant role of RND pumps has been associated to MDR phenotypes. Full article
Review
Ever-Adapting RND Efflux Pumps in Gram-Negative Multidrug-Resistant Pathogens: A Race against Time
Antibiotics 2021, 10(7), 774; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics10070774 - 25 Jun 2021
Viewed by 595
Abstract
The rise in multidrug resistance (MDR) is one of the greatest threats to human health worldwide. MDR in bacterial pathogens is a major challenge in healthcare, as bacterial infections are becoming untreatable by commercially available antibiotics. One of the main causes of MDR [...] Read more.
The rise in multidrug resistance (MDR) is one of the greatest threats to human health worldwide. MDR in bacterial pathogens is a major challenge in healthcare, as bacterial infections are becoming untreatable by commercially available antibiotics. One of the main causes of MDR is the over-expression of intrinsic and acquired multidrug efflux pumps, belonging to the resistance-nodulation-division (RND) superfamily, which can efflux a wide range of structurally different antibiotics. Besides over-expression, however, recent amino acid substitutions within the pumps themselves—causing an increased drug efflux efficiency—are causing additional worry. In this review, we take a closer look at clinically, environmentally and laboratory-evolved Gram-negative bacterial strains and their decreased drug sensitivity as a result of mutations directly in the RND-type pumps themselves (from Escherichia coli, Salmonella enterica, Neisseria gonorrhoeae, Pseudomonas aeruginosa, Acinetobacter baumannii and Legionella pneumophila). We also focus on the evolution of the efflux pumps by comparing hundreds of efflux pumps to determine where conservation is concentrated and where differences in amino acids can shed light on the broad and even broadening drug recognition. Knowledge of conservation, as well as of novel gain-of-function efflux pump mutations, is essential for the development of novel antibiotics and efflux pump inhibitors. Full article
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