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Journal of Bacteriology, May 2003, p. 2999-3008, Vol. 185, No. 10
0021-9193/03/$08.00+0     DOI: 10.1128/JB.185.10.2999-3008.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Attenuation of Mycobacterium tuberculosis by Disruption of a mas-Like Gene or a Chalcone Synthase-Like Gene, Which Causes Deficiency in Dimycocerosyl Phthiocerol Synthesis

Tatiana D. Sirakova,1 Vinod S. Dubey,1 Michael H. Cynamon,2 and Pappachan E. Kolattukudy1*

Departments of Biochemistry and Molecular and Cellular Biochemistry and Neurobiotechnology Center, Ohio State University, Columbus, Ohio 43210,1 Department of Medicine, Veterans Affairs Medical Center, Syracuse, New York 132102

Received 13 December 2002/ Accepted 18 February 2003

Tuberculosis is one of the leading preventable causes of death. Emergence of drug-resistant tuberculosis makes the discovery of new targets for antimycobacterial drugs critical. The unique mycobacterial cell wall lipids are known to play an important role in pathogenesis, and therefore the genes responsible for their biosynthesis offer potential new targets. To assess the possible role of some of the genes potentially involved in cell wall lipid synthesis, we disrupted a mas-like gene, msl7, and a chalcone synthase-like gene, pks10, with phage-mediated delivery of the disruption construct, in which the target gene was disrupted by replacement of an internal segment with the hygromycin resistance gene (hyg). Gene disruption by allelic exchange in the case of each disruptant was confirmed by PCR and Southern blot analyses. Neither msl7 nor pks10 mutants could produce dimycocerosyl phthiocerol, although both could produce mycocerosic acids. Thus, it is concluded that these gene products are involved in the biosynthesis of phthiocerol. Both mutants were found to be attenuated in a murine model, supporting the hypothesis that dimycocerosyl phthiocerol is a virulence factor and thus the many steps involved in its biosynthesis offer potential novel targets for antimycobacterial therapy.

* Corresponding author. Present address: Biomolecular Science Center and Department of Molecular Biology and Microbiology, University of Central Florida, Biomolecular Science Building, 4000 Central Florida Blvd., Orlando, FL 32816. Phone: (407) 823-1206. Fax: (407) 823-3095. E-mail: pk{at}mail.ucf.edu.

Journal of Bacteriology, May 2003, p. 2999-3008, Vol. 185, No. 10
0021-9193/03/$08.00+0     DOI: 10.1128/JB.185.10.2999-3008.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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