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Antimicrobial Agents and Chemotherapy, October 2009, p. 4138-4146, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00162-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Arabinosyltransferase EmbC Is Inhibited by Ethambutol in Mycobacterium tuberculosis{triangledown}

R. Goude,1,{dagger} A. G. Amin,2 D. Chatterjee,2 and T. Parish1,3*

Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, E1 2AT, United Kingdom,1 Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, Colorado 80523,2 Infectious Disease Research Institute, Seattle, Washington 981043

Received 5 February 2009/ Returned for modification 9 March 2009/ Accepted 8 July 2009

Ethambutol (EMB) is an antimycobacterial drug used extensively for the treatment of tuberculosis caused by Mycobacterium tuberculosis. EMB targets the biosynthesis of the cell wall, inhibiting the synthesis of both arabinogalactan and lipoarabinomannan (LAM), and is assumed to act via inhibition of three arabinosyltransferases: EmbA, EmbB, and EmbC. EmbA and EmbB are required for the synthesis of arabinogalactan, and at least one enzyme (M. tuberculosis EmbA [EmbAMt]) is essential in M. tuberculosis. EmbCMt is also essential for the viability of M. tuberculosis but is involved in the synthesis of LAM. We show that mutations in EmbCMt that reduce its arabinosyltransferase activity result in increased sensitivity to EMB and the production of smaller LAM species in M. tuberculosis. Overexpression of EmbCMt was not tolerated in M. tuberculosis, but overexpression of Mycobacterium smegmatis EmbC (EmbCMs) led to EMB resistance and the production of larger LAM species in M. tuberculosis. Treatment of wild-type M. tuberculosis strains with EMB led to inhibition of LAM synthesis, resulting in the production of smaller species of LAM. In contrast, no change in LAM production was seen in EMB-resistant strains. Overexpression of EmbBMs in M. tuberculosis also resulted in EMB resistance, but at a lower level than that caused by EmbCMs. Overexpression of EmbAMt in M. tuberculosis had no effect on EMB resistance. Thus, there is a direct correlation between EmbC activity and EMB resistance, as well as between EmbC activity and the size of the LAM species produced, confirming that EmbC is one of the cellular targets of EMB action.

* Corresponding author. Mailing address: Infectious Disease Research Institute, 1124 Columbia St., Suite 400, Seattle, WA 98104. Phone: (206) 330-2525. Fax: (206) 381-3678. E-mail: tparish{at}idri.org

{triangledown} Published ahead of print on 13 July 2009.

{dagger} Present address: CNRS UMR6026 DUALS, Université de Rennes I, Campus de Beaulieu, Bat13, Avenue du Général Leclerc, 35042 Rennes Cedex, France.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4138-4146, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00162-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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