Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps.
Nat Commun
; 13(1): 115, 2022 01 10.
Article
en En
| MEDLINE
| ID: mdl-35013254
ABSTRACT
Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas de Transporte de Membrana
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Piperazinas
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Piridinas
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Proteínas de la Membrana Bacteriana Externa
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Proteínas de Escherichia coli
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Proteínas Asociadas a Resistencia a Múltiples Medicamentos
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Escherichia coli
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Lipoproteínas
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Antibacterianos
Idioma:
En
Año:
2022
Tipo del documento:
Article