Inhibition studies of Mycobacterium tuberculosis salicylate synthase (MbtI).
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.
School of Chemistry, The University of Sydney, NSW 2006, Australia.
Alexandra
A
Manos-Turvey
Esther M M
EM
Bulloch
Peter J
PJ
Rutledge
Edward N
EN
Baker
J Shaun
JS
Lott
Richard J
RJ
Payne
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D002827:Chorismic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D008190:Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D014376:Tuberculosis / Q000188:drug therapy
D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C052985:isochorismic acid; D008190:Lyases; C022620:salicylate synthetase; D002827:Chorismic Acid