Discovery of venediols by activation of a silent type I polyketide biosynthetic gene cluster in Streptomyces venezuelae ATCC 15439

The genus of Streptomyces plays an indispensable role in discovery of bioactive secondary metabolites. As a model strain, Streptomyces venezuelae ATCC 15439 possesses more than 30 biosynthetic gene clusters (BGCs) in its genome; however, many of which are transcriptionally silent and hence uncharacterized. Here, we apply CRISPR/Cas9 genome editing technology to activate a cryptic type I polyketide biosynthetic gene cluster by site-specific insertion of the constitutive promoter kasOp∗, leading to the discovery of two new polyketide metabolites including venediols A (1) and B (2). The elucidated structures and heterologous expression of this BGC suggest an unusual loss of colinearity of the modular polyketide synthases during their biosynthesis.