Use and discovery of chemical elicitors that stimulate biosynthetic gene clusters in Streptomyces bacteria.

Secondary metabolite production from Streptomyces bacteria is primarily controlled at the level of transcription. Under normal laboratory conditions, the majority of the biosynthetic pathways of Streptomyces coelicolor are transcriptionally silent. These are often referred to as "cryptic" pathways and it is thought that they may encode the biosynthesis of yet unseen natural products with novel structures that may be valuable leads for therapeutics and as bioactive compounds. Sequencing of microbial genomes has supported the notion that cryptic pathways are widely distributed and likely to be a source of new chemical diversity. Hence, techniques that can reverse the silencing will be valuable for natural product screening as well as giving access to interesting new biology. We have focused on the identification of chemical elicitors capable of inducing expression of secondary metabolic gene clusters and to do so have drawn a parallel with fungal biology where inhibitors of histone acetylation change chromatin structure to derepress biosynthetic pathways. Similarly, we find that the same chemicals can also modify the expression of pathways in S. coelicolor and other Streptomyces spp. They variously act to increase expression from known pathways as well as inducing cryptic pathways. We hypothesize that nucleoid structure may be playing an analogous role to fungal chromatin structure in controlling transcriptional programs. Further, we speculate that microbial natural product collections could themselves be a rich source of new histone deacetylase inhibitors that have many applications in human health, such as anticancer therapeutics, beyond their traditional use as antimicrobials.