Molecular Interactions of Cephalosporins with the Deep Binding Pocket of the RND Transporter AcrB.
J Phys Chem B
; 123(22): 4625-4635, 2019 06 06.
Article
em En
| MEDLINE
| ID: mdl-31070373
ABSTRACT
The drug/proton antiporter AcrB, part of the major efflux pump AcrABZ-TolC in Escherichia coli, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multidrug resistance phenotype. However, the molecular features differentiating between good and poor substrates of the pump have yet to be identified. In this work, we combined molecular docking with molecular dynamics simulations to study the interactions between AcrB and two representative cephalosporins, cefepime and ceftazidime (a good and poor substrate of AcrB, respectively). Our analysis revealed different binding preferences of the two compounds toward the subsites of the large deep binding pocket of AcrB. Cefepime, although less hydrophobic than ceftazidime, showed a higher affinity than ceftazidime for the so-called hydrophobic trap, a region known for binding inhibitors and substrates. This supports the hypothesis that surface complementarity between the molecule and AcrB, more than the intrinsic hydrophobicity of the antibiotic, is a feature required for the interaction within this region. Oppositely, the preference of ceftazidime for binding outside the hydrophobic trap might not be optimal for triggering allosteric conformational changes needed to the transporter to accomplish its function. Altogether, our findings could provide valuable information for the design of new antibiotics less susceptible to the efflux mechanism.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Cefalosporinas
/
Proteínas de Escherichia coli
/
Proteínas Associadas à Resistência a Múltiplos Medicamentos
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Simulação de Dinâmica Molecular
/
Simulação de Acoplamento Molecular
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
J Phys Chem B
Assunto da revista:
QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Itália