title: Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site.
abstract: Mycobacterium tuberculosis salicylate synthase (MbtI) catalyses the first committed step in the biosynthesis of mycobactin T, an iron-chelating siderophore essential for the virulence and survival of M. tuberculosis. Co-crystal structures of MbtI with members of a first generation inhibitor library revealed large inhibitor-induced rearrangements within the active site of the enzyme. This plasticity of the MbtI active site was probed via the preparation of a library of inhibitors based on a 2,3-dihydroxybenzoate scaffold with a range of substituted phenylacrylate side chains appended to the C3 position. Most compounds exhibited moderate inhibitory activity against the enzyme, with inhibition constants in the micromolar range, while several dimethyl ester variants possessed promising anti-tubercular activity in vitro.
authors.affiliation: School of Chemistry, Building F11, The University of Sydney, Camperdown, NSW 2006, Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Manos-Turvey
authors.forename: Katie M
authors.initials: KM
authors.lastname: Cergol
authors.forename: Noeris K
authors.initials: NK
authors.lastname: Salam
authors.forename: Esther M M
authors.initials: EM
authors.lastname: Bulloch
authors.forename: Gamma
authors.initials: G
authors.lastname: Chi
authors.forename: Angel
authors.initials: A
authors.lastname: Pang
authors.forename: Warwick J
authors.initials: WJ
authors.lastname: Britton
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: West
authors.forename: Edward N
authors.initials: EN
authors.lastname: Baker
authors.forename: J Shaun
authors.initials: JS
authors.lastname: Lott
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Payne
mesh_terms: D000179:Acrylates / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004952:Esters; D062385:Hydroxybenzoates / Q000737:chemistry*; D007700:Kinetics; D008190:Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000179:Acrylates; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D004952:Esters; D062385:Hydroxybenzoates; D054852:Small Molecule Libraries; C009135:2,3-dihydroxybenzoic acid; D008190:Lyases; C022620:salicylate synthetase