Encountering Small-Molecule Biologicals in Genomic Space

Recent advances in understanding the logic of small-molecule evolution, construction and deployment in the biosphere have made it possible to approach the discovery of nature’s small-molecule biologicals, also known as natural products, in a fundamentally new way.  In this new paradigm, the DNA encoding a hallmark feature of a small-molecule biological, this being responsible for biosynthesis, regulation, or resistance, is used as a search probe for biosynthetic gene clusters sharing this conserved feature.  Sequence comparisons of these clusters first encountered in genomic space with known clusters enables binning into rediscoveries and novel relatives of the known family member(s).  Finally, engineered over-expression of the cluster provides the small-molecule biological in quantities sufficient for mechanism-of-action studies.  This new paradigm parallels in many ways the discovery and process used in the post-millennial era for discovery of novel proteinaceous biologicals.  Progress in this area at Warp Drive Bio will be discussed.