Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active siteElectronic supplementary information (ESI) available: 1H and 13C NMR spectra of all novel compounds and molecular dockings of 25-38. See DOI: 10.1039/c2ob26736e

• Main Authors: Manos-Turvey, Alexandra, Cergol, Katie M, Salam, Noeris K, Bulloch, Esther M. M, Chi, Gamma, Pang, Angel, Britton, Warwick J, West, Nicholas P, Baker, Edward N, Lott, J. Shaun, Payne, Richard J
• Format: Journal Article
• Language: English
• Published: 07.11.2012
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c2ob26736e

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 . Inhibitors of Mycobacterium tuberculosis salicylate synthase are described using co-crystal structures to guide inhibitor design.