S70: Sequence-based approaches to natural product discovery

Traditional approaches to microbial natural product discovery generally involve isolating and culturing strains, generating extracts, and using bioassays to guide the isolation of active compounds.  These methods are limited to the compounds expressed under a given set of culture conditions, generally require screening a large number of strains, and rely heavily on chance discovery.  Increased access to low cost genome sequencing has provided new opportunities to assess the biosynthetic potential of strains prior to chemical analysis.  This approach provides a method to target the products of pathways that have been prioritized based on bioinformatic analysis and thus reduces the element of chance in the discovery process.  Sequence data also provides unprecedented opportunities to study the distribution of biosynthetic pathways among individual strains and insight into the complex evolutionary processes that generate new chemical diversity.  We have been addressing these concepts using the marine actinomycete genus Salinsipora as a model organism.  Employing the bioinformatics tool NaPDoS, we have analyzed the genome sequences of 100 Salinispora strains derived from global collection sites.  The results reveal remarkable levels of biosynthetic diversity, the vast majority of which has been recently acquired, is distributed among a limited number of strains, and has not been linked to a structurally characterized metabolite.  This data set provides opportunities to target metabolites produced via specific biosynthetic mechanisms or that belong to sought after structural classes.  A variety of approaches are being applied to identify the products of these pathways, the results of which will be presented here.