NEW DRUGS FOR OPPORTUNISTIC INFECTIOUS DISEASES

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The objective of this project is to discover new prototype antibiotics with potential utility specifically for the treatment of AIDS-related opportunistic disseminated mycoses and mycobacteriosis. Acquired immunodeficiency Syndrome (AIDS) is characterized by a breakdown in the immune system which is manifested in the form of serious opportunistic infections. Treatment of such infections is often inadequate for a variety of reasons, including lack of effective antimicrobial therapy. Historically, most bacterial infections and localized fungal infections have been effectively treated with one of the numerous clinically available antibiotics. However, the need for new, more effective and less toxic antibiotics for the treatment of disseminated fungal and mycobacterial infections is obvious in light of the significant toxicities and failure rates of the currently available agents. The discovery of new antibiotics has in the past successfully relied primarily upon the isolation of such agents from natural sources. The major advantage of this approach over chemical synthesis or modification of existing agents is the likelihood of identifying new prototype drugs with quite different chemical structures, and hence, less likelihood of similar toxicities, cross-resistance, and mechanisms of action. Although microorganisms have traditionally served as the primary source of new antibiotics, it has recently been shown that higher plants also serve as sources for a number of diverse and novel antimicrobial agents. The goal of the project, to identify prototype antibiotics for AIDS related 01, will be accomplished by the initial in vitro evaluation of antifungal and antimycobacterial activity of extracts of higher plants. Plant extracts which show good activity will be fractionated and purified using a bioassay-directed scheme. This approach ensures that relatively little time and effort will be wasted in isolating inactive materials. Pure active compounds with significant minimum inhibitory concentrations (MIC) and relatively low in vitro cytotoxicity to mammalian cells will be evaluated for in vivo efficacy in established animal models of disseminated mycosis and mycobacteriosis in order to determine their potential clinical utility.