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JAC Advance Access originally published online on May 18, 2004
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Journal of Antimicrobial Chemotherapy (2004) 53, 1072-1075
© 2004 The British Society for Antimicrobial Chemotherapy

Role for malonyl coenzyme A:acyl carrier protein transacylase (MCAT) in the growth-inhibitory effect of the calmodulin antagonist trifluoperazine in Mycobacterium bovis BCG

Indrajit Sinha* and Thomas Dick§

Mycobacterium Biology Laboratory, Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Republic of Singapore

Received 27 January 2004; returned 17 February 2004; revised 8 March 2004; accepted 18 March 2004

Objectives: To determine whether the fatty acid synthesis enzyme malonyl coenzyme A:acyl carrier protein transacylase (MCAT) is involved in the growth-inhibitory effect of trifluoperazine in the tubercle bacillus Mycobacterium bovis BCG.

Methods: BCG was grown in liquid culture with various concentrations of trifluoperazine and growth was monitored by OD measurement. To determine the effect of trifluoperazine on MCAT protein level, total protein was extracted from BCG cultures and was analysed by 2D gel electrophoresis and western blot. To confirm trifluoperazine-dependent reduction in the MCAT protein level, two BCG strains overexpressing MCAT at a low and high constitutive level were similarly tested. The synergic effect of trifluoperazine and isoniazid was tested at sub-MIC levels in liquid cultures.

Results: Trifluoperazine inhibition of growth correlates with reduction in the steady-state level of MCAT protein. Overexpression of MCAT confers resistance to trifluoperazine. Trifluoperazine acts synergically (albeit weakly) with isoniazid and no resistance towards isoniazid alone was observed due to overexpression of MCAT. This suggests MCAT to be a specific target of trifluoperazine.

Conclusion: These results indicate MCAT as a target of trifluoperazine and provide an explanation for the inhibitory effect of trifluoperazine on mycobacterial lipid synthesis observed earlier. This makes MCAT a potential target for new antimycobacterials.

Keywords: fatty acid synthesis, M. bovis, antimycobacterials

* Corresponding author. Tel: +65-6874-6861; Fax: +65-6779-1117; E-mail: sinhai{at}imcb.nus.edu.sg

§ Present address. Novartis Institute for Tropical Diseases Pte Ltd, 1 Science Park Road, 04-14 The Capricorn, Singapore Science Park II, Singapore 117528, Republic of Singapore.


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