Deciphering the steps of prodiginine biosynthesis

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DESCRIPTION (provided by applicant): Prodiginines are a family of linear and cyclic oligopyrrole red-pigmented antibiotics produced by actinomycetes and other eubacteria. Members of this class of antibiotics have been known for some time, as have their broad antifungal, antibacterial activity. There has been a dramatic interest in recent years in these natural products as they appear to have pronounced antimalarial, anticancer and immunosuppressant activity. We have used a series of genetic and biochemical experiments to reveal that a cluster of 23 red genes in Streptomyces coelicolor genome encode a fascinating and unusual pathway leading to formation of undecylprodiginine and a cyclized derivative, streptorubin B. The initial stages of this process involve a complex interface with fatty acid biosynthesis which will be further investigated in specific aim 1. Subsequent stages involve numerous multifunctional and monofunctional proteins with unusual architecture and catalytic activities and specific aims 2-4 will be a continuation of our studies on these. Our preliminary work has also demonstrated that we can generate novel cyclic and linear prodiginine analogues in S. coelicolor by either feeding analogues of pathway intermediates to the appropriate blocked mutants, or creation of hybrid biosynthetic pathways (exchanging Red proteins with proteins of similar catalytic activity but different substrate specificities). Specific aim 5 will build on these successes generating additional novel prodiginine structures and evaluating their biological activity in antimalarial, immunosuppressant, anticancer and antifungal assays. A wide array of chemical, genetic and biochemical approaches will be used for these 5 specific aims which address our long term objective of a) building a comprehensive understanding of the enzymology of prodiginine biosynthetic pathways and b) using this knowledge to generate novel linear and cyclic prodiginines structures for potential application in human health. Lay Language Description. Some bacteria produce bright red pigments (prodiginines) which show promise for numerous human health applications including cancer treatment, fighting malaria and other infectious diseases, and helping organ transplant patients. This work will identify how these prodiginines are made by the bacteria and use this knowledge to generate and identify new prodiginines with the correct chemical properties and biological activities for possible clinical development.