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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.

Original publication




Journal article


Organic & biomolecular chemistry

Publication Date





9223 - 9236


School of Chemistry, Building F11, The University of Sydney, Camperdown, NSW 2006, Australia.


Mycobacterium tuberculosis, Acrylates, Esters, Lyases, Bacterial Proteins, Enzyme Inhibitors, Crystallography, X-Ray, Magnetic Resonance Spectroscopy, Microbial Sensitivity Tests, Catalytic Domain, Protein Binding, Structure-Activity Relationship, Drug Design, Kinetics, Models, Molecular, Microbial Viability, Small Molecule Libraries, Hydroxybenzoates