Research is proposed to continue the isolation and definition of new antitumor and antibiotic metabolites from marine microorganisms. This renewal application is a collaborative effort which utilizes the marine microbial resources and experience available at the Scripps Institution of Oceanography and the biological testing expertise provided by the Preclinical Anticancer Research Group at Bristol-Myers Company. During the renewal period, a specific focus will be placed upon both free living and symbiotic marine bacteria from unique marine habitats. Studies will be undertaken to isolate microorganisms from hypersaline environments, from deep ocean habitats and from near shore aerobic and anaerobic marine sediments. While a focus will be placed upon the development of anticancer agents with unusual chemical structures, we will enlarge upon our biotesting program in the areas f antimicrobial and antiviral chemotherapy. In particular, we will initiate the submission of samples to NCI and the Bristol-Myers Company for anti-HIV biotesting. The following are specific research components proposed for this renewal period: -We will continue to refine the isolation methods and culture and nutrient requirements for obligate marine bacterial to facilitate the (more) routine fermentation of these organisms. We will continue to add to our existing microorganism culture collection to provide a resource for others wishing to access these interesting organisms. -We will isolate over 1,000 microorganisms per year, focussing upon the unicellular and filamentous bacteria from unique marine environments. Cultures will be prescreened at Scripps using antibacterial, antifungal and genotoxin assays (SOS Chromatest), and the promising bacteria will be investigated further by Bristol-Myers Company. A series of mechanism-based biochemical assays, and in vitro cytotoxicity measurements against B-16 murine melanoma and HCT-116 human colon carcinoma, will be utilized to identify promising microorganisms. Bacteria will be re-fermented, the cultures will be retested in in vivo assays, and the antitumor constituents of the extracts will be isolated and structurally defined by contemporary spectral and chemical methods. -Existing bacteria already confirmed to produce potent cytotoxins or antibiotics, in particular strains CNB-083, CNB-132, CNB-139, CNB-164, CNB- 204 and CNB-225, will be pursued. New projects will be identified and prioritized as the discovery process continues. It is anticipated that approximately 20 active leads can be chemically investigated per year.
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