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

Four unreported aromatic polyketides CA049 A-D (-) were discovered in sp. HDN154049 through CdgB overexpression, an enzyme involved in c-di-GMP biosynthesis. Among them, compound contains a novel tricyclic aromatic scaffold appended with an α-pyranone ring, while compound represents the first example of a benzo-[]-xanthene skeleton derived from microbiological sources, and it displayed cytotoxic activity against the L-02 cancer cell line (IC = 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.