Ternary complex formation of AFN-1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies.
Chem Biol Drug Des
; 96(2): 704-713, 2020 08.
Article
en En
| MEDLINE
| ID: mdl-32227402
ABSTRACT
Acinetobacter baumannii is an opportunistic Gram-negative bacterial pathogen, associated mostly with hospital-acquired infections. The emergence of drug resistance strains made it necessary to explore new pathways for the development of more effective antibiotics. Enoyl CoA reductase (FabI), a key enzyme in the fatty acid biosynthesis (FAS) pathway, has emerged as a potential target for antibacterial drug development. Earlier reports show that the lead SaFabI inhibitor AFN-1252 can inhibit FabI from other organisms including Escherichia coli and Burkholderia pseudomallei, but with differential potency. In the present work, we show that AFN-1252 is a moderate inhibitor of AbFabI with an IC50 of 216 nM. AFN-1252 stabilized AbFabI with a 4.2°C increase in the melting temperature (Tm ) and, interestingly, the stabilization effect was significantly increased in presence of the cofactor NADH (∆Tm = 17°C), suggesting the formation of a ternary complex AbFabI AFN-1252 NADH. X-ray crystallography studies of AbFabI co-crystalized with AFN-1252 and NADH confirmed the ternary complex formation. The critical interactions of AFN-1252 with AbFabI and NADH identified from the co-crystal structure may facilitate the design and development of new drugs against A. baumannii infections by targeting the FAS pathway.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pironas
/
Benzofuranos
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Infecciones por Acinetobacter
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Acinetobacter baumannii
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Inhibidores Enzimáticos
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Ácido Graso Desaturasas
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Antibacterianos
/
NAD
Límite:
Humans
Idioma:
En
Revista:
Chem Biol Drug Des
Asunto de la revista:
BIOQUIMICA
/
FARMACIA
/
FARMACOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
India