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

Research output: Contribution to journalArticlepeer-review

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Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB. / Reading, Eamonn; Ahdash, Zainab; Fais, Chiara; Ricci, Vito; Wang-Kan, Xuan; Grimsey, Elizabeth; Stone, Jack; Malloci, Giuliano; Lau, Andy M; Findlay, Heather; Konijnenberg, Albert; Booth, Paula J; Ruggerone, Paolo; Vargiu, Attilio V; Piddock, Laura J V; Politis, Argyris.

In: Nature Communications, Vol. 11, No. 1, 04.11.2020, p. 5565.

Research output: Contribution to journalArticlepeer-review

Harvard

Reading, E, Ahdash, Z, Fais, C, Ricci, V, Wang-Kan, X, Grimsey, E, Stone, J, Malloci, G, Lau, AM, Findlay, H, Konijnenberg, A, Booth, PJ, Ruggerone, P, Vargiu, AV, Piddock, LJV & Politis, A 2020, 'Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB', Nature Communications, vol. 11, no. 1, pp. 5565. https://doi.org/10.1038/s41467-020-19397-2

APA

Reading, E., Ahdash, Z., Fais, C., Ricci, V., Wang-Kan, X., Grimsey, E., Stone, J., Malloci, G., Lau, A. M., Findlay, H., Konijnenberg, A., Booth, P. J., Ruggerone, P., Vargiu, A. V., Piddock, L. J. V., & Politis, A. (2020). Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB. Nature Communications, 11(1), 5565. https://doi.org/10.1038/s41467-020-19397-2

Vancouver

Author

Reading, Eamonn ; Ahdash, Zainab ; Fais, Chiara ; Ricci, Vito ; Wang-Kan, Xuan ; Grimsey, Elizabeth ; Stone, Jack ; Malloci, Giuliano ; Lau, Andy M ; Findlay, Heather ; Konijnenberg, Albert ; Booth, Paula J ; Ruggerone, Paolo ; Vargiu, Attilio V ; Piddock, Laura J V ; Politis, Argyris. / Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB. In: Nature Communications. 2020 ; Vol. 11, No. 1. pp. 5565.

Bibtex

@article{6513de1d4526485bb7e19908dcea5f92,
title = "Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB",
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.",
author = "Eamonn Reading and Zainab Ahdash and Chiara Fais and Vito Ricci and Xuan Wang-Kan and Elizabeth Grimsey and Jack Stone and Giuliano Malloci and Lau, {Andy M} and Heather Findlay and Albert Konijnenberg and Booth, {Paula J} and Paolo Ruggerone and Vargiu, {Attilio V} and Piddock, {Laura J V} and Argyris Politis",
year = "2020",
month = nov,
day = "4",
doi = "10.1038/s41467-020-19397-2",
language = "English",
volume = "11",
pages = "5565",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Springer",
number = "1",

}

RIS

TY - JOUR

T1 - Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB

AU - Reading, Eamonn

AU - Ahdash, Zainab

AU - Fais, Chiara

AU - Ricci, Vito

AU - Wang-Kan, Xuan

AU - Grimsey, Elizabeth

AU - Stone, Jack

AU - Malloci, Giuliano

AU - Lau, Andy M

AU - Findlay, Heather

AU - Konijnenberg, Albert

AU - Booth, Paula J

AU - Ruggerone, Paolo

AU - Vargiu, Attilio V

AU - Piddock, Laura J V

AU - Politis, Argyris

PY - 2020/11/4

Y1 - 2020/11/4

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-020-19397-2

DO - 10.1038/s41467-020-19397-2

M3 - Article

C2 - 33149158

VL - 11

SP - 5565

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

ER -