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Journal of Bacteriology, June 2005, p. 4173-4186, Vol. 187, No. 12
0021-9193/05/$08.00+0     doi:10.1128/JB.187.12.4173-4186.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Requirement of the mymA Operon for Appropriate Cell Wall Ultrastructure and Persistence of Mycobacterium tuberculosis in the Spleens of Guinea Pigs

Amit Singh,1,{dagger} Radhika Gupta,1 R. A. Vishwakarma,2 P. R. Narayanan,3 C. N. Paramasivan,3 V. D. Ramanathan,3 and Anil K. Tyagi1*

Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi 110021, India,1 National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India,2 Tuberculosis Research Centre, Mayor V. R. Ramanathan Road, Chetput, Chennai 600031, India3

Received 17 November 2004/ Accepted 3 March 2005

We had recently reported that the mymA operon (Rv3083 to Rv3089) of Mycobacterium tuberculosis is regulated by AraC/XylS transcriptional regulator VirS (Rv3082c) and is important for the cell envelope of M. tuberculosis. In this study, we further show that a virS mutant (Mtb{Delta}virS) and a mymA mutant (Mtbmym::hyg) of M. tuberculosis exhibit reduced contents and altered composition of mycolic acids along with the accumulation of saturated C24 and C26 fatty acids compared to the parental strain. These mutants were markedly more susceptible to major antitubercular drugs at acidic pH and also showed increased sensitivity to detergent (sodium dodecyl sulfate) and to acidic stress than the parental strain. We show that disruption of virS and mymA genes impairs the ability of M. tuberculosis to survive in activated macrophages, but not in resting macrophages, suggesting the importance of the mymA operon in protecting the bacterium against harsher conditions. Infection of guinea pigs with Mtb{Delta}virS, Mtbmym::hyg, and the parental strain resulted in an ~800-fold-reduced bacillary load of the mutant strains compared with the parental strain in spleens, but not in the lungs, of animals at 20 weeks postinfection. Phenotypic traits were fully complemented upon reintroduction of the virS gene into Mtb{Delta}virS. These observations show the important role of the mymA operon in the pathogenesis of M. tuberculosis at later stages of the disease.

* Corresponding author. Mailing address: Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, New Delhi 110021, India. Phone: 91-11-26881970. Fax: 91-11-26885270. E-mail: akt1000{at}hotmail.com.

{dagger} Present address: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294.

Journal of Bacteriology, June 2005, p. 4173-4186, Vol. 187, No. 12
0021-9193/05/$08.00+0     doi:10.1128/JB.187.12.4173-4186.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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