NOVEL ANTITUBERCULAR AGENTS VIA COMBINATORIAL CHEMISTRY

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Tuberculosis is the leading cause of global mortality by an infectious disease, account for over 3 million deaths. The rate of infection is an estimated 8 million individuals per year, with 21,337 cases diagnosed in the United States in 1996 (CDC). Chemotherapy had great diminished the incidence of this disease in industrialized nations. The emergence of multidrug resistant strains of Mycobacterium tuberculosis and HIV-infected individuals with secondary infections of tuberculosis are having a worldwide impact on the epidemiology of these infectious agents. Mycobacteria possess remarkable intrinsic resistance to antimicrobial agents mediated by their unique cell wall composition. Treatment of tuberculosis requires the administration of multiple agents for months, which affects patient compliance, and ultimately the development of drug resistance. The CDC reports that greater than or equal to 75 percent of tuberculosis cases diagnosed in the United States (1996) were resistant to at least one drug. Combinatorial chemistry, in conjunction with high- throughput screening provides a new opportunity for drug discovery in this increasing important therapeutic area. A novel reporter assay for the identification of inhibitors of mycolic acid biosynthesis, an essential component of the mycobacterial cell wall has been developed. This assay will be used in a screen of an encoded combinatorial chemical collection, representing 1.6 million compounds. Proposed commercial applications: The goal of this research is the identification of novel antitubercular agents that act by inhibiting cell biosynthesis. A novel high-throughput assays has been development for screening large combinatorial chemical libraries comprising 1.6 million compounds. The development of a clinical, candidate resulting from the optimization of lead structures is the potential commercial application of this project.