S82: A sequence-based approach to natural product discovery

Microbial natural product discovery has traditionally involved cultivation, extraction and testing for biological activity followed by bioassay-guided isolation and structure elucidation of the active constituents.  These methods proved highly successful in the early days of microbial natural product discovery but have become increasingly ineffective due to the high rates of known compound rediscovery.  Ready access to DNA sequence data coupled with advances in our understanding to the molecular genetics of natural product biosynthesis provide new opportunities to incorporate sequence analysis into the discovery process.  The web tool Natural Product Domain Seeker (NaPDoS) provides a rapid method to evaluate the genetic potential of bacteria to produce polyketide synthase (PKS) or non-ribosomal peptide synthetase (NRPS) derived secondary metabolites.  Input data can include PCR products, draft or complete genomes, or metagenomic datasets.  Ketosynthase (KS) and condensation (C) domains from PKS and NRPS genes, respectively, are identified and aligned to an in house database derived from experimentally characterized biosynthetic pathways.  NaPDoS rapidly classifies these domains into functional types and, in cases where close matches are identified, offers predictions about the potential compounds produced.  Sequences can be output in a variety of formats and phylogenetic analyses performed to confirm identity based classification.  NaPDoS provides a rapid mechanism to evaluate the biosynthetic richness and novelty of strains prior to chemical analysis.  This approach provides opportunities to reduce the redundant isolation of previously described compounds and identify strains (or environments) with the greatest potential to produce new secondary metabolites prior to initiation of chemical or biological screening.