Title

Attenuation of Mycobacterium tuberculosis by disruption of a mas-like gene or a chalcone synthase-like gene, which causes deficiency in dimycocerosyl phthiocerol synthesis

Authors

Authors

T. D. Sirakova; V. S. Dubey; M. H. Cynamon;P. E. Kolattukudy

Abbreviated Journal Title

J. Bacteriol.

Keywords

MYCOCEROSIC ACID SYNTHASE; BACILLUS-CALMETTE-GUERIN; POLYKETIDE; SYNTHASE; BIOSYNTHESIS; IDENTIFICATION; ENVELOPE; CLUSTER; COMPLEX; CLONING; Microbiology

Abstract

Tuberculosis is one of the leading preventable causes of death. Emergence of drug-resistant tuberculosis makes the discovery of new targets for antimyrobacterial 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.

Journal Title

Journal of Bacteriology

Volume

185

Issue/Number

10

Publication Date

1-1-2003

Document Type

Article

Language

English

First Page

2999

Last Page

3008

WOS Identifier

WOS:000182686900004

ISSN

0021-9193

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