Bacterial Multidrug Efflux Transporters

Delmar, Jared A.; Su, Chih‐Chia; Yu, Edward

doi:10.1146/annurev-biophys-051013-022855

Cited by 159 publications

(139 citation statements)

References 133 publications

(198 reference statements)

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“…The resistance/nodulation/cell division (RND) family transporters, AMP efflux pumps that are present in many Gram-negative bacteria, have been studied for some time [139,140]. A typical member of this family is composed of three components: an inner membrane proton/ AMP antiporter, an OM transporter and a periplasmic accessory protein that completes and stabilizes the entire efflux complex [141,142].…”

Section: Efflux Pumpsmentioning

confidence: 99%

Bacterial strategies of resistance to antimicrobial peptides

Joo

Otto

2016

Phil. Trans. R. Soc. B

284

238

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One contribution of 13 to a theme issue 'Evolutionary ecology of arthropod antimicrobial peptides'. Antimicrobial peptides (AMPs) are a key component of the host's innate immune system, targeting invasive and colonizing bacteria. For successful survival and colonization of the host, bacteria have a series of mechanisms to interfere with AMP activity, and AMP resistance is intimately connected with the virulence potential of bacterial pathogens. In particular, because AMPs are considered as potential novel antimicrobial drugs, it is vital to understand bacterial AMP resistance mechanisms. This review gives a comparative overview of Gram-positive and Gram-negative bacterial strategies of resistance to various AMPs, such as repulsion or sequestration by bacterial surface structures, alteration of membrane charge or fluidity, degradation and removal by efflux pumps.This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'.

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Section: Efflux Pumpsmentioning

confidence: 99%

Bacterial strategies of resistance to antimicrobial peptides

Joo

Otto

2016

Phil. Trans. R. Soc. B

284

238

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“…These pumps are often responsible for limiting macrolide spectrum in Gram-negative species and overexpression of multidrug efflux pumps is associated with clinically relevant drug resistance in both Gram-negative and Gram-positive species. Interested readers are referred to recent reviews (Costa et al 2013;Blair et al 2014;Delmar et al 2014;Sun et al 2014).…”

mentioning

confidence: 99%

Resistance to Macrolide Antibiotics in Public Health Pathogens

Fyfe

Grossman

Kerstein

et al. 2016

Cold Spring Harb Perspect Med

172

140

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Macrolide resistance mechanisms can be target-based with a change in a 23S ribosomal RNA (rRNA) residue or a mutation in ribosomal protein L4 or L22 affecting the ribosome's interaction with the antibiotic. Alternatively, mono-or dimethylation of A2058 in domain V of the 23S rRNA by an acquired rRNA methyltransferase, the product of an erm (erythromycin ribosome methylation) gene, can interfere with antibiotic binding. Acquired genes encoding efflux pumps, most predominantly mef(A) þ msr(D) in pneumococci/streptococci and msr(A/B) in staphylococci, also mediate resistance. Drug-inactivating mechanisms include phosphorylation of the 2 0 -hydroxyl of the amino sugar found at position C5 by phosphotransferases and hydrolysis of the macrocyclic lactone by esterases. These acquired genes are regulated by either translation or transcription attenuation, largely because cells are less fit when these genes, especially the rRNA methyltransferases, are highly induced or constitutively expressed. The induction of gene expression is cleverly tied to the mechanism of action of macrolides, relying on antibiotic-bound ribosomes stalled at specific sequences of nascent polypeptides to promote transcription or translation of downstream sequences. Macrolide antibiotics are polyketides composed of a 14-, 15-, or 16-membered macrocyclic lactone ring (14-, 15-, and 16-membered) to which several sugars and/or side chains have been attached by the producing organism or as modifications during semisynthesis in the laboratory (Figs. 1 and 2). Newer semisynthetic derivations, like ketolides telithromycin, and solithromycin, have a C3-keto group in place of the C3 cladinose (akin to naturally occurring pikromycin) (Brockmann and Henkel 1950) and an 11,12-cyclic carbamate with an extended alkyl -aryl side chain that increases the affinity of the antibiotic for the ribosome by 10-to 100-fold (Hansen et al. 1999;Dunkle et al. 2010); in the case of solithromycin, a fluorine substituent at C2 provides an additional ribosomal interaction (Llano-Sotelo et al. 2010). Macrolides continue to be important in the therapeutic treatment of community-acquired pneumonia (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and atypicals Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae), sexually transmitted diseases (Neiserria gonorhoeae, Chlamydia trachomatis, Mycoplasma genitalium), shigellosis, and salmonellosis. With solithromycin heading for a new drug application (NDA) filing in 2016 and having the in vitro potency to treat erythromycin-resistant

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“…Efflux also affects biocidal agents comprising disinfectants, antiseptics, and preservatives that are commonly practiced in medicine [11,12]. Moreover, it is also involved in bacterial colonization and virulence [10,[13][14][15][16] and contributes to the acquisition of additional mechanisms of resistance that includes the mutation in antibiotic targets (e.g. mutation in gyrase/topoisomerase for quinolone) or the production of enzymes that degrade antibiotics (e.g.…”

mentioning

confidence: 99%

Multidrug efflux pumps and their role in antibiotic and antiseptic resistance: a pharmacodynamic perspective

Alibert

Diarra

Hernandez

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: Worrying levels of bacterial resistance have been reported worldwide involving the failure of many available antibiotic treatments. Multidrug resistance (MDR) in Gram-negative bacteria is often ascribed to the presence of multiple and different resistance mechanisms in the same strain. RND efflux pumps play a major role and are an attractive target to discover new antibacterial drugs. Areas covered: This review discusses the prevalence of efflux pumps, their overexpression in clinical scenarios, their polyselectivity, their effect on the intracellular concentrations of various antibiotics associated with the alteration of the membrane permeability and their involvement in pathogenicity are discussed. Expert opinion: Efflux pumps are new targets for the development of adjuvant in antibiotic treatments by of efflux pump inhibition. They may allow us to rejuvenate old antibiotics acting on their concen-tration inside the bacteria and thus potentiating their activity while blocking the release of virulence factors. It is a pharmacodynamic challenge to finalize new combined therapy. KEYWORDSEfflux pump; Gram-negative bacteria; antibiotic; multidrug resistance; inhibitor Article highlights• Efflux pumps play a major role in multidrug resistance in Gram-negative bacteria • The pharmacodynamic role of RND efflux pumps in antibiotic resis-tance opens up new perspectives to alternative therapeutics • Targeting efflux pumps consists in solving the problems of polyse-lectivity, drug accumulation, membrane permeability and pathogeni-city related to bacterial resistance mechanisms • How to validate efflux pumps as target for new combined therapy?• Efflux pump inhibitor could be used as adjuvant in antibiotic treatments

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Bacterial Multidrug Efflux Transporters

Cited by 159 publications

References 133 publications

Bacterial strategies of resistance to antimicrobial peptides

Bacterial strategies of resistance to antimicrobial peptides

Resistance to Macrolide Antibiotics in Public Health Pathogens

Multidrug efflux pumps and their role in antibiotic and antiseptic resistance: a pharmacodynamic perspective

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