The purpose of this Program Project is to bring together collective expertise in the areas of molecular biology, biochemistry and immunology, and in vitro and in vivo models of mycobacterial disease, in order to accumulate fundamental knowledge leading to a better understanding of the nature of Mycobacterium avium, including the identification of drug targets, whereby colonization and subsequent disseminated disease in AIDS patients can be successfully treated. Project 1 will pursue the biochemistry of M. avium in order to provide a detailed chemical knowledge of the cell wall barrier, including those components unique to the group of mycobacterial which may comprise specific drug targets. In addition, it will investigate the basis of colony morphotypes, including the growing body of evidence that relates the expression of the glycopeptidolipids to persistence and virulence of the infection and resistance to chemotherapy. Project 2 will address similar problems at the genomic level, specifically, the cloning and analysis of genes for potential drug targets including genes that encode essential enzyme systems and control the synthesis of structures that determine morphotype, and hence potentially contribute to the virulence of the organism and pathogenesis of disease. Project 3 will continue to develop innovative animal models of M. avium infection, models that most closely mimic the clinical situation in immunodeficient AIDS patients. It will document the pathological process of colonization, leading to active infection and disseminated disease in T cell-deficient mice, and will relate this information to the molecular, biochemical, and morphological properties of the isolate or variant. In addition, it will provide a resource for the in vivo testing of potentially efficacious compounds identified in Project 4. This last Project will directly address the question of identifying drugs with activity against specific targets, by combining computer modeling techniques with a sophisticated panel of in vitro activity assays, prior to the testing of such agents in animal models of infection.
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