Structural and enzymatic analyses reveal the binding mode of a novel series of Francisella tularensis enoyl reductase (FabI) inhibitors

J Med Chem. 2012 Jun 28;55(12):5933-41. doi: 10.1021/jm300489v. Epub 2012 Jun 8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism*
  • Anti-Bacterial Agents / pharmacology*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / metabolism
  • Benzimidazoles / pharmacology
  • Catalytic Domain
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / antagonists & inhibitors*
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / chemistry
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / metabolism*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Francisella tularensis / drug effects
  • Francisella tularensis / enzymology*
  • Inhibitory Concentration 50
  • Kinetics
  • Models, Molecular
  • NAD / metabolism
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Benzimidazoles
  • Enzyme Inhibitors
  • NAD
  • benzimidazole
  • Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)

Associated data

  • PDB/3UIC