Tuberculosis has been classified as an emerging and re-emerging infectious disease. Contributing to its public health importance is the co-existing progression of the AIDS pandemic and the development of drug-resistant strains of Mycobacterium tuberculosis. This has lead to the recognition that more needs to be learned about essential metabolic pathways of the organism to provide a factual basis for the development of new antibiotics. This project addresses this question, proposing experiments designed to identify biosynthetic components of the metabolic pathway of mycolic acids, essential molecules of the M. tuberculosis cell wall. The research plan calls for the use of two new technologies of the """"""""post-genomic era"""""""": use of the complete annotated M. tuberculosis genome and mRNA gene response profiling by microarray competitive hybridization. Microarray-based results will be complemented by biochemical and mutational studies performed in collaboration with Drs. Patrick Brennan and Brigitte Gicquel, respectively. In the terminal phase of this study, newly-identified mycolic acid biosynthetic enzymes will be examined in a group of isogenic pairs of strains which have evolved from isoniazid-sensitive to isoniazid-resistant during treatment. If successful, these studies should provide new information about mechanisms of drug-action and drug-resistance and suggest novel drug targets within the mycolic acid metabolic pathway.
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