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

Eamonn Reading (), Zainab Ahdash, Chiara Fais, Vito Ricci, Xuan Wang-Kan, Elizabeth Grimsey, Jack Stone, Giuliano Malloci, Andy M. Lau, Heather Findlay, Albert Konijnenberg, Paula J. Booth, Paolo Ruggerone, Attilio V. Vargiu, Laura J. V. Piddock and Argyris Politis ()
Additional contact information
Eamonn Reading: Department of Chemistry, King’s College London, Britannia House
Zainab Ahdash: Department of Chemistry, King’s College London, Britannia House
Chiara Fais: University of Cagliari, Cittadella Universitaria, S.P. Monserrato-Sestu
Vito Ricci: The University of Birmingham
Xuan Wang-Kan: The University of Birmingham
Elizabeth Grimsey: The University of Birmingham
Jack Stone: The University of Birmingham
Giuliano Malloci: University of Cagliari, Cittadella Universitaria, S.P. Monserrato-Sestu
Andy M. Lau: Department of Chemistry, King’s College London, Britannia House
Heather Findlay: Department of Chemistry, King’s College London, Britannia House
Albert Konijnenberg: Thermo Fisher Scientific
Paula J. Booth: Department of Chemistry, King’s College London, Britannia House
Paolo Ruggerone: University of Cagliari, Cittadella Universitaria, S.P. Monserrato-Sestu
Attilio V. Vargiu: University of Cagliari, Cittadella Universitaria, S.P. Monserrato-Sestu
Laura J. V. Piddock: The University of Birmingham
Argyris Politis: Department of Chemistry, King’s College London, Britannia House

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19397-2

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