M. tuberculosis Cell Wall Biogenesis; New Drugs; TB-HIV

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DESCRIPTION (provided by applicant): The incidence of HIV-associated tuberculosis has been increasing worldwide since the beginning of the AIDS epidemic, and is expected to rise even further in the future, especially in developing countries. The accelerating and amplifying influence of HIV infection is contributing to the increasing incidence of disease caused by multidrug-resistant strains of Mycobacterium tuberculosis. Development of new drugs against tuberculosis is thus important for control of both of the infections. Mycobacterial cell wall is an attractive target for rational drug design against tuberculosis, due to the fact that it forms a protective, almost impermeable barrier, on the surface of mycobacteria. Some of the most effective drugs currently used for the treatment of TB affect components of its backbone - mycolylarabinogalactan-peptidoglycan (mAGP) complex. Our long-term goal is to identify processes and enzymes involved in the mAGP assembly. Possible AG biosynthetic gene cluster has been recently identified in the genome of M. tuberculosis and thus the specific aims of this grant proposal are: 1. Identify the genes involved in mycobacterial galactan biosynthesis within AG biosynthetic cluster and determine their biological functions via cloning, overexpression and subsequent biochemical characterization. 2. Establish the function of the putative ABC transporter within the AG biosynthetic cluster by way of preparation and phenotypic characterization of the mutants/conditional mutants. The approach will help define one of the more complex pathways in microbial biochemistry and reveal reactions that should be exploitable for drug development. The research will be primarily carried out at Comenius University, Faculty of Natural Sciences in Bratislava, Slovakia in collaboration with Katarina Mikusova, as an extension of the NIH grant A1-18357.