Structural and Enzymatic Analyses Reveal the Binding Mode of a Novel Series of Francisella tularensis Enoyl Reductase (FabI) Inhibitors

Journal Article · Mon Aug 24 04:00:00 EDT 2020 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm300489v· OSTI ID:1047900

Mehboob, Shahila; Hevener, Kirk E; Truong, Kent; Boci, Teuta; Santarsiero, Bernard D; Johnson, Michael E ^[1]

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1. UIC

Because of structural and mechanistic differences between eukaryotic and prokaryotic fatty acid synthesis enzymes, the bacterial pathway, FAS-II, is an attractive target for the design of antimicrobial agents. We have previously reported the identification of a novel series of benzimidazole compounds with particularly good antibacterial effect against Francisella tularensis, a Category A biowarfare pathogen. Herein we report the crystal structure of the F. tularensis FabI enzyme in complex with our most active benzimidazole compound bound with NADH. The structure reveals that the benzimidazole compounds bind to the substrate site in a unique conformation that is distinct from the binding motif of other known FabI inhibitors. Detailed inhibition kinetics have confirmed that the compounds possess a novel inhibitory mechanism that is unique among known FabI inhibitors. These studies could have a strong impact on future antimicrobial design efforts and may reveal new avenues for the design of FAS-II active antibacterial compounds.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: UNIVERSITYNIH
• OSTI ID: 1047900
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: (12) ; 06, 2012 Vol. 55; ISSN JMCMAR; ISSN 0022-2623
• Country of Publication: United States
• Language: ENGLISH