Genome mining based on transcriptional regulatory networks uncovers a novel locus involved in desferrioxamine biosynthesis

Abstract

Bacteria produce a plethora of natural products that are in clinical, agricultural and biotechnological use. Genome mining has uncovered millions of biosynthetic gene clusters (BGCs) that encode their biosynthesis, the vast majority of them lacking a clear product or function. Thus, a major challenge is to predict the bioactivities of the molecules these BGCs specify, and how to elicit their expression. Here, we present an innovative strategy whereby we harness the power of regulatory networks combined with global gene expression patterns to predict BGC functions. Bioinformatic analysis of all genes predicted to be controlled by the iron master regulator DmdR1 combined with co-expression data, led to identification of the novel operon desJGH that plays a key role in the biosynthesis of the iron overload drug desferrioxamine (DFO) B in Streptomyces coelicolor. Deletion of either desG or desH strongly reduces the biosynthesis of DFO B, while that of DFO E is enhanced. DesJGH most likely act by changing the balance between the DFO precursors. Our work shows the power of harnessing regulation-based genome mining to functionally prioritize BGCs, accelerating the discovery of novel bioactive molecules.