Mining microbial genomes for new natural products and biosynthetic pathways

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK Correspondence Gregory L. Challis G.L.Challis{at}warwick.ac.uk Analyses of microbial genome sequences have revealed numerous examples of ‘cryptic’ or ‘orphan’ biosynthetic gene clusters, with the potential to direct the production of novel, structurally complex natural products. This article summarizes the various methods that have been developed for discovering the products of cryptic biosynthetic gene clusters in microbes and gives an account of my group's discovery of the products of two such gene clusters in the model actinomycete Streptomyces coelicolor M145. These discoveries hint at new mechanisms, roles and specificities for natural product biosynthetic enzymes. Our efforts to elucidate these are described. The identification of new secondary metabolites of S. coelicolor raises the question: what is their biological function? Progress towards answering this question is also summarized. Abbreviations: A, adenylation; ACP, acyl carrier protein; CDA, calcium-dependent antibiotic; FAS, fatty acid synthase; fhOrn, N 5 -formyl- N 5 -hydroxyornithine; hOrn, N 5 -hydroxyornithine; NRPS, nonribosomal peptide synthetase; PCP, peptidyl carrier protein; PKS, polyketide synthase; TE, thioesterase