1. Ternary complex formation of AFN‐1252 with Acinetobacter baumannii FabI and NADH: Crystallographic and biochemical studies.
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Rao, Narasimha K, Nataraj, Vijayashankar, Ravi, Mohan, Panchariya, Love, Palai, Kirttija, Talapati, Sumalatha R., Lakshminarasimhan, Anirudha, Ramachandra, Murali, and Antony, Thomas
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GRAM-negative bacteria , *BURKHOLDERIA pseudomallei , *ACINETOBACTER baumannii , *NOSOCOMIAL infections , *X-ray crystallography , *DRUG development - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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