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Identification of 2-aminothiazole-4-carboxylate derivatives active against Mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH

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Author(s)

Qosay Al-Balas, Nahoum G. Anthony, Bilal Al-Jaidi, Amani Alnimr, Grainne Abbott, Alistair K. Brown, Rebecca C. Taylor, Gurdyal S. Besra, Timothy D. McHugh, Stephen H. Gillespie, Blair F. Johnston, Simon P. Mackay, Geoffrey D. Coxon

School/Research organisations

Abstract

Background: Tuberculosis (TB) is a disease which kills two million people every year and infects approximately over one-third of the world's population. The difficulty in managing tuberculosis is the prolonged treatment duration, the emergence of drug resistance and co-infection with HIV/AIDS. Tuberculosis control requires new drugs that act at novel drug targets to help combat resistant forms of Mycobacterium tuberculosis and reduce treatment duration.

Methodology/Principal Findings: Our approach was to modify the naturally occurring and synthetically challenging antibiotic thiolactomycin (TLM) to the more tractable 2-aminothiazole-4-carboxylate scaffold to generate compounds that mimic TLM's novel mode of action. We report here the identification of a series of compounds possessing excellent activity against M. tuberculosis H37Rv and, dissociatively, against the beta-ketoacyl synthase enzyme mtFabH which is targeted by TLM. Specifically, methyl 2-amino-5-benzylthiazole-4-carboxylate was found to inhibit M. tuberculosis H37Rv with an MIC of 0.06 mu g/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)thiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95 +/- 0.05 mu g/ml (2.43 +/- 0.13 mu M) but was not active against the whole cell organism.

Conclusions/Significance: These findings clearly identify the 2-aminothiazole-4-carboxylate scaffold as a promising new template towards the discovery of a new class of anti-tubercular agents.

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Details

Original languageEnglish
Pages (from-to)e5617
Number of pages9
JournalPLoS ONE
Volume4
Issue number5
DOIs
Publication statusPublished - 19 May 2009

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