The Potential and Challenges of Cryptic Metabolites

Small molecules biosynthesized by environmental microbes – bacteria and fungi – have provided the molecular basis for the majority of therapeutic agents used as antibiotics, anticancer agents, and immune system modulators.  In spite of the historical success of this discovery paradigm, it has been largely abandoned by the pharmaceutical industry for many reasons including high rediscovery rates of known compounds.  Over the last decade, genomic sequences from both bacterial and fungal genomes have revealed that we typically discover ~10% of the genetic potential of producing organisms under standard laboratory conditions.  The remaining 10% are called ‘cryptic metabolites’, and their biosynthetic genes are called ‘orphan clusters’.  Finding cryptic metabolites, or deorphanizing clusters, has been pursued by several approaches, which will be discussed in this talk.  The failure of any robust algorithmic discovery paradigm to emerge from these efforts creates a significant opportunity for synthetic biology.