Perturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB.
Nat Commun
; 11(1): 5565, 2020 11 04.
Article
em En
| MEDLINE
| ID: mdl-33149158
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.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
3_ND
Base de dados:
MEDLINE
Assunto principal:
Proteínas Quinases
/
Ciprofloxacina
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Proteínas de Escherichia coli
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Proteínas Associadas à Resistência a Múltiplos Medicamentos
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Farmacorresistência Bacteriana Múltipla
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Dipeptídeos
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Escherichia coli
/
Proteínas de Membrana
Tipo de estudo:
Guideline
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2020
Tipo de documento:
Article