JAC Advance Access published online on November 12, 2005
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dki409
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1 Tuberculosis Research Lead Programme, Medical Research Council, Pretoria, South Africa
* To whom correspondence should be addressed. 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.
Received June 27, 2005
Revised September 23, 2005
Accepted October 14, 2005
Original article
Effects of clofazimine on potassium uptake by a Trk-deletion mutant of Mycobacterium tuberculosis
M. C. Cholo 1,
H. I. Boshoff 2,
H. C. Steel 3,
R. Cockeran 3,
N. M. Matlola 4,
K. J. Downing 5,
V. Mizrahi 6,
and
R. Anderson 3 *
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 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; Present address. Schering-Plough (Pty) Ltd, Isando, Johannesburg, South Africa
5 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; Present address. Department of Molecular and Cell Biology, University of Cape Town, Rondebosch, South Africa
6 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
R. Anderson, E-mail: randerso{at}medic.up.ac.za
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