There continues to be a need for anti-cancer agents. The discovery of novel natural products has led to the identification of several candidates which may prove to be effective anti-cancer drugs, these include the marine natural product discodermolide which was isolated from a deep water lithistid sponge. Marine microorganisms are also providing to be a source of novel natural products however little is known about secondary metabolite expression in many of these organisms. It is the goal of this program project to express the genes from these microbes in Streptomyces venezuelae. This will allow the expression of secondary metabolite gens in a well defined system, it will also allow combinatorial biology to produce unnatural natural products. This novel source of potentially bioactive metabolites will be coupled with the Novartis anti-cancer drug discovery program in order to identify new anti-cancer agents. This project includes many functions which can most efficiently be handled by a single Core facility. To this end the core laboratory at HBOI will perform the DNA extractions, fermentations and extraction of fermentation broths which are central to this project. Microorganisms will be provided to the Core laboratory from the research projects at HBOI, the University of Oregon, and UCSC for DNA extraction. The purified DNA will be shipped to the University of Minnesota where the molecular biology will be performed. The resultant clones will be shipped back to the Core laboratory where they will be fermented at a small scale, extracted and the extracts shipped to Novartis for screening. The target for throughput is 20,000 clines in year one and 30,000 in subsequent years. Clones which show activity in the Novartis screens will be refermented to confirm the production of a bioactive compound of interest. All fermentations to produce material for bioassay-guided purification of the active component will be performed by the individual research groups.
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