Inhibition studies of Mycobacterium tuberculosis salicylate synthase (MbtI)

ChemMedChem. 2010 Jul 5;5(7):1067-79. doi: 10.1002/cmdc.201000137.

Abstract

Mycobacterium tuberculosis salicylate synthase (MbtI), a member of the chorismate-utilizing enzyme family, catalyses the first committed step in the biosynthesis of the siderophore mycobactin T. This complex secondary metabolite is essential for both virulence and survival of M. tuberculosis, the etiological agent of tuberculosis (TB). It is therefore anticipated that inhibitors of this enzyme may serve as TB therapies with a novel mode of action. Herein we describe the first inhibition study of M. tuberculosis MbtI using a library of functionalized benzoate-based inhibitors designed to mimic the substrate (chorismate) and intermediate (isochorismate) of the MbtI-catalyzed reaction. The most potent inhibitors prepared were those designed to mimic the enzyme intermediate, isochorismate. These compounds, based on a 2,3-dihydroxybenzoate scaffold, proved to be low-micromolar inhibitors of MbtI. The most potent inhibitors in this series possessed hydrophobic enol ether side chains at C3 in place of the enol-pyruvyl side chain found in chorismate and isochorismate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / chemistry*
  • Antitubercular Agents / therapeutic use
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Chorismic Acid / chemical synthesis
  • Chorismic Acid / chemistry
  • Chorismic Acid / therapeutic use
  • Computer Simulation
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Lyases / antagonists & inhibitors*
  • Lyases / metabolism
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / enzymology*
  • Tuberculosis / drug therapy

Substances

  • Antitubercular Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • isochorismic acid
  • Lyases
  • salicylate synthetase
  • Chorismic Acid