A novel potent metal-binding NDM-1 inhibitor was identified by fragment virtual, SPR and NMR screening.
Bioorg Med Chem
; 28(9): 115437, 2020 05 01.
Article
em En
| MEDLINE
| ID: mdl-32229085
ABSTRACT
NDM-1 can hydrolyze nearly all available ß-lactam antibiotics, including carbapenems. NDM-1 producing bacterial strains are worldwide threats. It is still very challenging to find a potent NDM-1 inhibitor for clinical use. In our study, we used a metal-binding pharmacophore (MBP) enriched virtual fragment library to screen NDM-1 hits. SPR screening helped to verify the MBP virtual hits and identified a new NDM-1 binder and weak inhibitor A1. A solution NMR study of 15N-labeled NDM-1 showed that A1 disturbed all three residues coordinating the second zinc ion (Zn2) in the active pocket of NDM-1. The perturbation only happened in the presence of zinc ion, indicating that A1 bound to Zn2. Based on the scaffold of A1, we designed and synthesized a series of NDM-1 inhibitors. Several compounds showed synergistic antibacterial activity with meropenem against NDM-1 producing K. pneumoniae.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Zinco
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Beta-Lactamases
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Inibidores Enzimáticos
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Complexos de Coordenação
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Klebsiella pneumoniae
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Antibacterianos
Tipo de estudo:
Diagnostic_studies
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Screening_studies
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article