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JAC Advance Access originally published online on November 12, 2005
Journal of Antimicrobial Chemotherapy 2006 57(1):79-84; doi:10.1093/jac/dki409
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Effects of clofazimine on potassium uptake by a Trk-deletion mutant of Mycobacterium tuberculosis

M. C. Cholo1, H. I. Boshoff2, H. C. Steel3, R. Cockeran3, N. M. Matlola3,{dagger}, K. J. Downing4,{ddagger}, V. Mizrahi4 and R. Anderson3,*

1 Tuberculosis Research Lead Programme, Medical Research Council, Pretoria, South Africa; 2 Tuberculosis Research Section, NIAID, National Institutes of Health, Rockville, MD, USA; 3 Medical Research Council Unit for Inflammation and Immunity, Department of Immunology, Faculty of Health Sciences, University of Pretoria and Tshwane Academic Division of the National Health Laboratory Service, South Africa; 4 MRC/NHLS/WITS Molecular Mycobacteriology Research Unit, DST-NRF Centre of Excellence for Biomedical Research, School of Pathology, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa

Received 27 June 2005; returned 8 September 2005; revised 23 September 2005; accepted 14 October 2005

* Corresponding author. Tel: +27-12-319-2425; Fax: +27-12-323-0732; E-mail: randerso{at}medic.up.ac.za

Objectives: This study was designed to investigate the effects of the membrane-active, anti-mycobacterial agent, clofazimine, on potassium (K+)-uptake by a mutant of Mycobacterium tuberculosis (MTB), in which the Trk system, the major K+ transporter of this microbial pathogen, had been selectively inactivated.

Methods: The ceoB and ceoC genes of MTB, which encode the TrkA proteins, CeoB and CeoC, were deleted by homologous recombination, and the double-knockout mutant and wild-type strains compared with respect to K+ uptake and growth in the presence and absence of clofazimine (0.015–2.5 mg/L) using radioassay procedures.

Results: Surprisingly, the magnitudes of K+ uptake and rate of growth of the ceoBC-knockout mutant were significantly (P < 0.05) greater than those of the wild-type strain, due, presumably, to induction of a back-up transporter. Exposure of both the wild-type strain and ceoBC-knockout mutant of MTB to clofazimine was accompanied by dose-related decreases in K+ uptake, as well as growth, which were of comparable magnitude for both strains.

Conclusions: These observations demonstrate that the major K+ transporter of MTB, Trk, as well as an uncharacterized inducible back-up system, is equally sensitive to the inhibitory actions of clofazimine.

Keywords: ceoB and ceoC genes , growth rate , uptake of rubidium


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