ROLE OF BACTERIA IN THE PRODUCTION OF BRYOSTATINS

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DESCRIPTION (verbatim from applicant's abstract): In many cases natural products from marine invertebrates are known or suspected to be biosynthesized by bacterial symbionts. The marine bryozoan Bugula neritina is the source of the bryostatins, a unique family of compounds with anticancer activity. B. neritina harbors a specific bacterial symbiont "Candidatus Endobugula sertula." We hypothesize that the biosynthetic source of bryostatins in B. neritina is the bacterial symbiont "Candidatus Endobugula sertula." Our long-term objectives are: 1) to investigate the role of microbial symbionts in the biosynthesis of marine natural products, 2) to develop methods to exploit symbionts and their biosynthetic genes for economical and environmentally sound production of drugs derived from marine natural products, and 3) to investigate and exploit biosynthetic pathways of marine microorganisms to produce known and novel structures. The specific aims are: 1) to determine the biosynthetic origin of bryostatins in B. neritina. 2) To clone the biosynthetic genes for byrostatins in and express them in a heterologous host. 3) To cultivate any bacterial symbionts identified as a source of bryostatins and induce expression of bryostatin production in culture. The bryostatins are complex polyketides, a chemical family that contains many compounds with diverse and potent biological activities. The bryostatins have potential for treatment of cancer and other diseases; bryostatin 1 is in Phase II clinical trials for cancer treatment. The chief obstacle to development of bryostatins is lack of supply. Our project aims to solve this problem by either 1) cloning the genes for the biosynthetic pathway and expressing them in a heterologous host, or 2) cultivating a bryostatin-producing symbiont. The research approach will be to localize bryostatin biosynthesis within the bryozoan, clone polyketide synthase genes, and express them in a Streptomyces host. In addition, we will use a novel approach to optimize cultivation conditions to isolate "E. sertula" in culture.