New Methodologies for Accelerating Natural Product Discovery

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 DESCRIPTION (provided by applicant): Secondary metabolites are the origin of a large fraction of drugs used to successfully treat life threatening-illnesses. Because secondary metabolites, their derivatives, or compounds inspired by them are so widespread in the clinic, there remains great enthusiasm for their continued discovery. However, enthusiasm for the work of secondary metabolite discovery has waned because after decades of mining our environment for drug candidates, easily accessible ecosystems have been exhausted, and the methods for discovery currently employed are extremely labor intensive, with a low per-organism compound yield, and the revelation of new chemical diversity has apparently slowed down. However, the recent advent of inexpensive genome sequencing technology has demonstrated unambiguously that efforts to date only scratch the surface of the available natural chemical diversity. Whereas most organisms have generally yielded one or two natural products, genomics has informed us that these same organisms contain the genetic blueprints for many more - ten or twenty times more. But to date few if any facile generalizable methods for eliciting the translation of these blueprints into molecules in tubes have been provided. Herein we tackle two major objectives of opening new ecosystems to natural product discovery and removing the expression bottleneck to accelerate natural product discovery in microorganisms from unusual sources. To accomplish these goals we develop new instrumental, analytical, bioinformatics, and biostatistical methods to capture the information in a comprehensive microbial metabolome that is relevant to new compound discovery and chemical ecology. Our three aims in support of these objectives encompass three major specific aims which are (1) Chemical biogeological survey of secondary metabolism in hypogean (cave) ecosystems, (2) to develop native metabolic activation of biosynthetic processes for discovery, (3) provide an atlas of stimulus to genotype for rational selection of chemical and biological conditions that induce secondary metabolism in organisms with high apparent biosynthetic aptitude. The successful completion of the proposed research is highly relevant to human health because it will provide methods to accelerate the identification of natural products which have had and continue to have a large impact on human health. Furthermore, the discovery of the mode of action of newly discovered and rediscovered compounds for which mode of action has yet to be determined may provide new therapeutics.