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Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB.
- Source :
-
Nature communications [Nat Commun] 2020 Nov 04; Vol. 11 (1), pp. 5565. Date of Electronic Publication: 2020 Nov 04. - Publication Year :
- 2020
-
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.
- Subjects :
- Anti-Bacterial Agents chemistry
Anti-Bacterial Agents pharmacology
Binding Sites genetics
Biological Transport, Active drug effects
Biological Transport, Active genetics
Ciprofloxacin chemistry
Circular Dichroism
Deuterium chemistry
Dipeptides chemistry
Drug Resistance, Multiple, Bacterial drug effects
Escherichia coli genetics
Escherichia coli Proteins antagonists & inhibitors
Escherichia coli Proteins genetics
Escherichia coli Proteins metabolism
Ligands
Mass Spectrometry methods
Membrane Proteins antagonists & inhibitors
Membrane Proteins genetics
Membrane Proteins metabolism
Microbial Sensitivity Tests
Molecular Dynamics Simulation
Multidrug Resistance-Associated Proteins genetics
Multidrug Resistance-Associated Proteins metabolism
Mutation
Protein Kinases genetics
Protein Kinases metabolism
Ciprofloxacin pharmacology
Dipeptides pharmacology
Drug Resistance, Multiple, Bacterial genetics
Escherichia coli metabolism
Escherichia coli Proteins chemistry
Membrane Proteins chemistry
Multidrug Resistance-Associated Proteins chemistry
Protein Kinases chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33149158
- Full Text :
- https://doi.org/10.1038/s41467-020-19397-2