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Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB

Research output: Contribution to journalArticle

Eamonn Reading, Paula Booth, Andy Lau, Zainab Ahdash, Argyris Politis, Heather Findlay, Chiara Fais, Vito Ricci, Xuan Wang Kan, Elizabeth Grimsey, Jack Stone, Giuliano Malloci, Albert Konijnenberg, Paolo Ruggerone, Attilio V Vargiu, Laura JV Piddock

Original languageEnglish
Article number5565
JournalNature Communications
Volume11
Issue number1
DOIs
Published1 Dec 2020

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King's Authors

Abstract

Resistance-nodulation-division efflux pumps play a key role in inherent and evolved multidrug resistance in bacteria. AcrB, a prototypical member of this protein family, extrudes a wide-range of antimicrobial agents out of bacteria. Although high-resolution structures exist for AcrB, its conformational fluctuations and their putative role in function are largely unknown. Here, we determine these structural dynamics in the presence of substrates using hydrogen/deuterium exchange mass spectrometry, complemented by molecular dynamics simulations, and bacterial susceptibility studies. We show that an efflux pump inhibitor potentiates antibiotic activity by restraining drug-binding pocket dynamics, rather than preventing antibiotic binding. We also reveal that a drug-binding pocket substitution discovered within a multidrug resistant clinical isolate modifies the plasticity of the transport pathway, which could explain its altered substrate efflux. Our results provide insight into the molecular mechanism of drug export and inhibition of a major multidrug efflux pump and the directive role of its dynamics.

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