Metabolic Engineering Strategies Based on Secondary Messengers c‑di-GMP for the Discovery of Novel Aromatic Polyketides in Streptomyces sp. HDN154049.

Four unreported aromatic polyketides CA049 A-D (1-4) were discovered in Streptomyces sp. HDN154049 through CdgB overexpression, an enzyme involved in c-di-GMP biosynthesis. Among them, compound 1 contains a novel tricyclic aromatic scaffold appended with an α-pyranone ring, while compound 3 represents the first example of a benzo-[kl]-xanthene skeleton derived from microbiological sources, and it displayed cytotoxic activity against the L-02 cancer cell line (IC(50) = 6.71 μM). This work shows that adjusting the expression level of c-di-GMP could be an efficient method to increase the secondary metabolic production capacity of actinomycete strains.