Activation of silent biosynthetic gene clusters via rational manipulation of AHFCA-dependent regulatory networks

A key challenge in genomics-driven natural product discovery is the development of rational methods for inducing the expression of gene clusters that are expressed poorly, or not at all, in laboratory cultures. In 2008, we reported that 2-alkyl-4-hydroxymethylfuran-3-carboxylic acids (AHFCAs) induce the production of methylenomycin antibiotics in Streptomyces coelicolor. Based on an understanding of the way in which AHFCAs are biosynthesised in S. coelicolor and the role they play in regulating methylenomycin biosynthesis, we have identified several putative specialised metabolite biosynthetic gene clusters in other actinobacterial genomes that also appear to be controlled by AHFCA-dependent regulatory networks. Deletion of a repressor gene within such networks upregulates AHFCA production and appears to prolong the expression of biosynthetic genes under their control. These findings have been applied to induction of the expression of putative AHFCA-regulated biosynthetic gene clusters in other actinobacteria that are silent under laboratory growth conditions, resulting in the discovery of novel specialised metabolites.