The urgent need to develop new therapies for treating both sensitive and especially resistant strains of m. tuberculosis requires a return to basic research to define both the failures of existing treatments and new drug targets. Several well established anti-tuberculosis agents, such as INH, are known to inhibit mycolic acid biosynthesis and an initial screen for inhibitors of mycolic acid biosyntheses has been developed. Thus, a biochemical study (Project 1) coupled with a molecular genetic approach (Project 2) into the anabolic pathway of mycolic acids should provide fruitful leads in drug discovery (Project 3). Our immediate goals in project 1 are to define, dissect, and characterize the mycolate synthase complex through the use of sub-cellular fractionation and solubilization of activity; to purify individual enzymes of this pathways for the development in conjunction with SmithKline Beecham of high=through put screens to assay for potential inhibitors of mycolate biosynthesis; to examine the complex mechanism of mycolic acid transport and the mode of action of known anti- tuberculosis drugs in cell-free extracts of M. tuberculosis; to synthesize novel structurally related therapeutic agents as custom designed inhibitors of mycolate biosynthesis; to understand the entire biochemistry of mycolate synthesis and its relation to FAS complexes with a view to complementary """"""""structure-based-drug design"""""""" approaches. The combined efforts of this highly experienced consortium should provide the means to solve some of the problems associated with drug resistance through understanding mycolic acid biosynthesis and providing highly development enzymatic screens for inhibitors of mycolate biosynthesis.
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