Genome mining for the search and discovery of bioactive compounds: the Streptomyces paradigm

The need for new antimicrobials is indisputable. The flight from natural products in drug discovery was unfortunate; however, the revolution that is genome mining, enabled by the explosion in sequencing technology, is a cause for hope. Nevertheless, renewed search and discovery is still a challenge. We explore novel metabolite diversity and the challenges in Streptomyces. Estimating the extent of novel bioactive metabolites remaining to be discovered is an important driver for future investment. Frequent re-discovery of known natural products was a major factor in big pharma exiting search and discovery, and remains a reality. We explore whether this is due to exhaustive isolation and frequent lateral gene transfer. Analysing all biosynthetic gene clusters across all genomes is challenging. Therefore, representative examples of the patterns of secondary metabolite diversity suggest that re-discovery is linked to frequent expression in frequently isolated (and frequently misidentified) strains. Lateral gene transfer of complete biosynthetic clusters is less frequent than might be perceived but frequent gene exchange implies a massive combinatorial biosynthesis experiment. Genome sequencing emphasises rare expression of many secondary metabolite gene clusters and diversification at the finest levels of phylogenetic discrimination. In addition, we are only just beginning to unravel the impact of ecology. The hidden diversity suggests that cluster cloning and heterologous expression in microbial cell factories will explore this diversity more effectively.