Role of Bacteria in production of ET-743 in E. turbinata

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DESCRIPTION (provided by applicant): 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. Marine invertebrates are rich sources of bioactive metabolites, many of which are excellent candidates for drug development. Lack of supply is one of the most serious barriers to development of many of these compounds. In some cases, bacterial symbionts are hypothesized to be the true biosynthetic source of the compound. ET-743 is an anti-cancer drug from a marine ascidian, Ecteinascidia turbinata, that is suspected to be of symbiotic origin, and which is in Phase II clinical trials. One obstacle to exploring the full potential of ET-743 is lack of supply. Both aquaculture and semi-synthesis have been used to obtain the compound but neither are cost effective. We have developed a biosynthetic scheme for ET-743, based on the nonribosomal peptide synthetase genes for the closely related bacterial compound saframycin MX1 from Myxococcus xanthus. Furthermore, we have identified a bacterial symbiont, the possible source of ET-743, in E. turbinata. Our project aims to solve the supply problem by cultivating the ET-743 producing symbiont and/ or cloning the genes for the biosynthetic pathway to fulfill the long-term goal of expression in a heterologous host. The specific aims are to: 1. Identify, characterize and cultivate the ET-743 producing bacterial symbiont of E. turbinata 2. Identify and clone ET-743 biosynthetic pathway genes.