P137: Remodeling secondary metabolism with synthetic signals

The ‘secondary’ metabolism of the streptomycetes has provided many bioactive molecules that are used as drugs. This includes antibiotics, chemotherapeutic drugs, immune suppressants, and many others. Secondary metabolism remains poorly understood.  For example, we do not know how it is linked to primary metabolism or what its biological triggers are. This is important because most strains express only a small fraction of their secondary metabolites under laboratory conditions: most secondary metabolites in the sequenced bacterial genomes are of unknown structure and biological activity. Learning how to trigger their expression could lead to the discovery of new drugs.

We have taken a novel approach to this question by screening 30,000 synthetic compounds for molecules that can alter secondary metabolism in Streptomyces coelicolor. We identified 19 molecules that influence yields of the pigmented molecules actinorhodin and undecylprodigeosin. Interestingly, four of them, the ARC2 series, have closely related structures suggesting that they interact with the same target(s). In depth structure/function analysis and genetic experiments suggest that the mechanism of action of molecules is to directly influence fatty acid biosynthesis, thereby shunting precursors into secondary metabolism. This reveals one direct link between the secondary metabolites and primary metabolism. The other class of molecules, the ARC6 series, function by a distinct mechanism because they alter yields of a different spectrum of secondary metabolites than the ARC2 series. Importantly, both ARC2 and ARC6 remodel secondary metabolism in most streptomycetes and both ‘awaken’ distinct sets of cryptic metabolites.