Identification of 2-Aminothiazole-4-Carboxylate derivatives active against mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH

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

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

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. 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 β-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 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. 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.
LanguageEnglish
Article numbere5617
Number of pages9
JournalPLoS One
Volume4
Issue number5
DOIs
Publication statusPublished - 19 May 2009

Fingerprint

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase
Mycobacterium tuberculosis
tuberculosis
Tuberculosis
chemical derivatives
Derivatives
Scaffolds
Pharmaceutical Preparations
duration
new drugs
drug resistance
Coinfection
mixed infection
Drug Resistance
Inhibitory Concentration 50
inhibitory concentration 50
developing countries
mechanism of action
Acquired Immunodeficiency Syndrome
antibiotics

Keywords

  • tuberculosis
  • Mycobacterium tuberculosis
  • thiolactomycin
  • mtFabH

Cite this

Al-Balas, Qosay ; Anthony, Nahoum G. ; Al-Jaidi, Bilal ; Alnimr, Amani ; Abbott, Grainne ; Brown, Alistair K. ; Taylor, Rebecca C. ; Besra, Gurdyal S. ; McHugh, Timothy D. ; Gillespie, Stephen H. ; Johnston, Blair F. ; Mackay, Simon P. ; Coxon, Geoffrey D. / Identification of 2-Aminothiazole-4-Carboxylate derivatives active against mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH. In: PLoS One. 2009 ; Vol. 4, No. 5.
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abstract = "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. 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 β-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 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. 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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author = "Qosay Al-Balas and Anthony, {Nahoum G.} and Bilal Al-Jaidi and Amani Alnimr and Grainne Abbott and Brown, {Alistair K.} and Taylor, {Rebecca C.} and Besra, {Gurdyal S.} and McHugh, {Timothy D.} and Gillespie, {Stephen H.} and Johnston, {Blair F.} and Mackay, {Simon P.} and Coxon, {Geoffrey D.}",
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Identification of 2-Aminothiazole-4-Carboxylate derivatives active against mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH. / Al-Balas, Qosay; Anthony, Nahoum G.; Al-Jaidi, Bilal; Alnimr, Amani; Abbott, Grainne; Brown, Alistair K.; Taylor, Rebecca C.; Besra, Gurdyal S.; McHugh, Timothy D.; Gillespie, Stephen H.; Johnston, Blair F.; Mackay, Simon P.; Coxon, Geoffrey D.

In: PLoS One, Vol. 4, No. 5, e5617, 19.05.2009.

Research output: Contribution to journalArticle

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T1 - Identification of 2-Aminothiazole-4-Carboxylate derivatives active against mycobacterium tuberculosis H37Rv and the beta-ketoacyl-ACP synthase mtFabH

AU - Al-Balas, Qosay

AU - Anthony, Nahoum G.

AU - Al-Jaidi, Bilal

AU - Alnimr, Amani

AU - Abbott, Grainne

AU - Brown, Alistair K.

AU - Taylor, Rebecca C.

AU - Besra, Gurdyal S.

AU - McHugh, Timothy D.

AU - Gillespie, Stephen H.

AU - Johnston, Blair F.

AU - Mackay, Simon P.

AU - Coxon, Geoffrey D.

PY - 2009/5/19

Y1 - 2009/5/19

N2 - 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. 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 β-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 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. 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.

AB - 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. 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 β-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 µg/ml (240 nM), but showed no activity against mtFabH, whereas methyl 2-(2-bromoacetamido)-5-(3-chlorophenyl)t​hiazole-4-carboxylate inhibited mtFabH with an IC50 of 0.95±0.05 µg/ml (2.43±0.13 µM) but was not active against the whole cell organism. 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.

KW - tuberculosis

KW - Mycobacterium tuberculosis

KW - thiolactomycin

KW - mtFabH

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DO - 10.1371/journal.pone.0005617

M3 - Article

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JO - PLOS One

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