Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site

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 and Payne, Richard J. (2012) Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site. Organic and Biomolecular Chemistry, 10 46: 9223-9236. doi:10.1039/c2ob26736e


Author 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.
Title Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site
Journal name Organic and Biomolecular Chemistry   Check publisher's open access policy
ISSN 1477-0520
1477-0539
Publication date 2012-01-01
Year available 2012
Sub-type Article (original research)
DOI 10.1039/c2ob26736e
Open Access Status Not Open Access
Volume 10
Issue 46
Start page 9223
End page 9236
Total pages 14
Place of publication Cambridge, United Kingdom
Publisher Royal Society of Chemistry
Collection year 2012
Language eng
Formatted 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. 
Keyword Chorismate Utilizing Enzymes
Mycobactin Biosynthesis Pathway
Anthranilate Synthase
Isochorismate Synthase
Purification
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
 
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