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

SUBMITTER: Reading E 

PROVIDER: S-EPMC7642415 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature