New compounds via activation of secondary metabolite biosynthesis gene clusters in terrestrial and marine Streptomyces

Analyses of actinomycete bacteria genomes revealed an astounding number of gene clusters potentially governing biosynthesis of secondary metabolites that have not been discovered by conventional bioactivity screening. To explore this hidden potential for drug discovery, we aimed at activating such gene clusters by overexpressing cluster-associate regulators in the original hosts. First, we obtained high-quality genome sequence of Streptomyces noursei ATCC 11455 known as a producer of the medically important polyene macrolide nystatin, antibacterial glycosylated macrolide and albonoursin. antiSMASH 2.0 analysis of the genome revealed the presence of at least 38 gene clusters  potentially governing biosynthesis of secondary metabolites, including one for a tetramycin-like polyene macrolide. A putative transcriptional regulator gene from this cluster was overexpressed in the nystatin non-producing S. noursei, leading to production of a new tetraenic polyene macrolide, termed notromycin. Encouraged by this success, we then explored Streptomyces albus GBA94-07, a marine sponge-derived streptomycete carrying several unique biosynthetic gene clusters. Using the same strategy, we attempted to activate a putative peptidyl nucleoside biosynthetic gene cluster. Surprisingly, a series of new molecules was recovered from the fermentation broth of the activated strain that were shown to be deferoxamine-derived glycoconjugates not found in the control. These results represent an example of interplay between different biosynthetic pathways that can be exploited to generate new hybrid metabolites. The presented studies provide examples of genome-based bioprospecting that can revitalize drug discovery programs.