The role played by drug efflux pumps in bacterial multidrug resistance

Chitsaz, Mohsen; Brown, Melissa H.

doi:10.1042/ebc20160064

Cited by 90 publications

(63 citation statements)

References 83 publications

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“…The mechanisms of resistance mainly entail the production of drug inactivating enzymes, alteration of drug targets, mobile resistant genetic elements, and prevention of drug access; this last mechanism refers to the functions of drug efflux and influx (Du Toit, 2017). Efflux is a key mechanism of cellular responses to varied circumstances (Chitsaz and Brown, 2017) and plays a main role in a range of bacterial behaviors, including biofilm formation, quorum sensing, pathogenicity, and virulence. This mechanism allows bacterial cells to regulate their inner environments through the efflux of toxic substances, such as antimicrobial agents and metabolic products.…”

Section: Discussionmentioning

confidence: 99%

Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

et al. 2018

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The number of multidrug-resistant strains of Riemerella anatipestifer continues to increase, and new strategies for the treatment of associated infections are necessary. Recently, numerous studies have shown that efflux pumps (EPs) play key roles in universal bacterial mechanisms that contribute to antibiotic resistance. In addition, studies have shown that the effects of antibiotics that are subjected to efflux can be reinforced by their combined use with efflux pump inhibitors (EPIs). Unfortunately, the role of the efflux system in R. anatipestifer remains barely understood. In this study, we evaluated the role of EPs and resistance genes in the resistance generated by clinical strains of R. anatipestifer to antibiotics. A set of 10 R. anatipestifer strains were characterized by drug resistance, associated resistance genes, and antibiotic profiles in the presence and absence of EPIs. Efflux activity was studied on a real time basis through a fluorometric method. Quantification of the levels of mRNA transcription of efflux pump genes (EPGs) was determined by RT-qPCR. Several approaches (detection of resistance genes, drug susceptibility testing, and growth kinetics analysis) were used to assess the correlation between the effect of the EPIs and the resistance levels. Analysis of the R. anatipestifer growth inhibition tests showed that the antibiotic activity was enhanced by the synergy of EPIs. Among the various resistance genes that confer antibiotic resistance, different minimum inhibitory concentrations (MICs) were observed. The different levels of resistance were reduced by EPIs. Real time fluorometry showed that all the R. anatipestifer strains presented inherent efflux activity, conferring varying levels of inhibition in the presence of EPIs. Moreover, 15 EPGs were overexpressed in the presence of antibiotics. The addition of EPIs to antibiotics led to downregulation in the expression of some EPGs and a simultaneous increase in drug resistance and sensitivity. These results demonstrated the contribution of these EPs in the resistant phenotype of the clinical strains of R. anatipestifer that are under investigation, independently of the resistant genotype of the respective strains. Intrinsic efflux activity was possibly linked to the evolution of resistance in multidrug-resistant isolates of R. anatipestifer. Furthermore, the inhibition of EPs by EPIs could enhance the clinical effects of antibiotics.

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Section: Discussionmentioning

confidence: 99%

Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

et al. 2018

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“…Multi-Drug Resistant (MDR) pathogens represent one of the most pressing health concerns of the XXI Century due to their ability to elude the action of most (in some instances all) antibiotics (1)(2)(3)(4). A special family of membrane transport proteins, the so-called efflux pumps, plays a major role in conferring MDR by shuttling a broad spectrum of chemically unrelated cytotoxic molecules out of bacteria (5)(6)(7)(8)(9). Polyspecificity and partial overlap among the substrate specificities of different pumps are striking properties of these efflux machineries (10,11), making them a key survival tool of bacteria.…”

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confidence: 99%

Water-mediated interactions enable smooth substrate transport in a bacterial efflux pump

Vargiu

Ramaswamy

Malvacio

et al. 2017

Preprint

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Efflux pumps of the Resistance-Nodulation-cell Division superfamily confer multi-drug resistance to Gram-negative bacteria. AcrB of Escherichia coli is a paradigm model of these polyspecific transporters. The molecular determinants and the energetics of the functional rotation mechanism proposed for the export of substrates by this protein have not yet been unveiled. To this aim, we implemented an original protocol that allows mimicking substrate transport in silico. We show that the conformational changes occurring in AcrB enable the formation of a layer of structured waters on the surface of the substrate transport channel. This, in turn, allows for a fairly constant hydration of the substrate that facilitates its diffusion.Our findings reveal a new molecular mechanism of transport in polyspecific systems, whereby waters contribute by screening potentially strong substrate-protein interactions. The mechanistic understanding of a fundamental process related to multi-drug transport provided here could help rationalizing the behavior of other polyspecific systems.. CC-BY 4.0 International license not peer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was . http://dx.doi.org/10.1101/182683 doi: bioRxiv preprint first posted online 2 Multi-Drug Resistant (MDR) pathogens represent one of the most pressing health concerns of the XXI Century due to their ability to elude the action of most (in some instances all) antibiotics (1-4). A special family of membrane transport proteins, the so-called efflux pumps, plays a major role in conferring MDR by shuttling a broad spectrum of chemically unrelated cytotoxic molecules out of bacteria (5-9). Polyspecificity and partial overlap among the substrate specificities of different pumps are striking properties of these efflux machineries (10, 11), making them a key survival tool of bacteria.The efflux systems of the Resistance Nodulation-cell Division (RND) superfamily, which span the entire periplasm connecting the inner and the outer membranes, are mainly involved in the onset of MDR in Gram-negative bacteria (5, 12-14). The AcrABZ-TolC efflux pump of Escherichia coli is the paradigm model and the most studied RND efflux pump. It is composed of the outer membrane efflux duct TolC, the inner membrane-anchored adaptor protein AcrA, the small transmembrane protein AcrZ and the inner membrane RND protein AcrB (15). The lattermost is a drug/H + antiporter fuelled by the proton gradient across the inner membrane and involved in the recognition and translocation of a very broad range of compounds (16).The multi-drug recognition capabilities and the postulated efflux mechanism of RND transporters are linked through an intriguing structural puzzle, which raised the question of how these proteins achieve their special features. An important step in this direction was made with the publication of the structure of AcrB ( Figure 1A Successively, a second conformational change from T to O (supposed to be the energyrequi...

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“…RND efflux on A. baumannii has Journal of Biosciences and Medicines Figure 1. Structure of major families A. baumannii efflux pumps + PACE family a newly superfamily identify (adapted from [44] and [45]).…”

Section: Rnd Efflux Pumpsmentioning

confidence: 99%

Mechanisms Efflux Pumps of <i>Acinetobacter baumannii</i> (MDR): Increasing Resistance to Antibiotics

Temgoua¹,

Wu²

2019

JBM

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Acinetobacter baumannii has greatly increased its degree of resistance to become multidrug resistant (MDR) over the past 30 years and is on the red line of the most widely replicated bacteria according to World Health Organization (WHO). The efflux pumps are the main cause for the increasing antibiotic resistance of A. baumannii originated from nosocomial infection. The progressive resistance of A. baumannii even on the recent drugs (tigecycline and fosfomycin) reduces to very effective antibiotic scale. With attention focused on MDR and pan-drug-resistant (PDR) in A. baumannii multiple works on efflux pumps chemical inhibitor (NMP, PAβN, omeprazole, verapamil, reserpine, CCCP) are still in progress. Certain inhibitors from plants (Biricodar and timcodar, Falvone, Mahonia, Dalea versicolor, Lycopus europaeus, and Rosmarinus officinalis) have the capability to have such compounds according to their very significant synergistic effect with antibiotics. In this review we focused on the growth of antibiotic resistance to explain the mechanism of efflux pumps into these different super families and a comprehensive understanding of the extrusion, regulation and physiology role of drug efflux pumps in the essential development of anti-resistivity drugs. We recapitulated the evolution of the work carried out in these fields during the last years and in the course of elaboration, with the aim of increasing the chances of decreasing bacterial resistivity to antibiotics.

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The role played by drug efflux pumps in bacterial multidrug resistance

Cited by 90 publications

References 83 publications

Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

Water-mediated interactions enable smooth substrate transport in a bacterial efflux pump

Mechanisms Efflux Pumps of <i>Acinetobacter baumannii</i> (MDR): Increasing Resistance to Antibiotics

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The role played by drug efflux pumps in bacterial multidrug resistance

Cited by 90 publications

References 83 publications

Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

Interplay Between the Phenotype and Genotype, and Efflux Pumps in Drug-Resistant Strains of Riemerella anatipestifer

Water-mediated interactions enable smooth substrate transport in a bacterial efflux pump

Mechanisms Efflux Pumps of &lt;i&gt;Acinetobacter baumannii&lt;/i&gt; (MDR): Increasing Resistance to Antibiotics

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Mechanisms Efflux Pumps of <i>Acinetobacter baumannii</i> (MDR): Increasing Resistance to Antibiotics