Isolation of Verrucosins A-E from a Marine sp. Reveals a Unifying Biosynthetic Hypothesis for Linear and Macrocyclic Polyketides.

As part of our long-standing program evaluating the biosynthetic complexity and biomedical potential of natural products from marine microbes, our attention was drawn to culture extracts from a sp. (strain TAA-831), which produced multiple compounds with unique UV absorbance signatures and HRMS data. Large-scale fermentation and targeted isolation afforded verrucosins A-E (), a mixture of linear and macrocyclic polyketides whose structures were determined through a synergistic combination of experimental, computational, and genomic approaches. The conserved sequence of methyl malonate and malonate motifs across the verrucosins implied a shared biosynthetic origin despite structural divergence as linear and cyclic congeners. Targeted genome mining revealed a lone type I/type III hybrid polyketide synthase biosynthetic gene cluster, , that is likely responsible for verrucosin production. This revelation demonstrates for the first time that linear 3,5-dihydroxybenzenic ( and ) and cyclic ansamycin () polyketides can be naturally produced by a single biosynthetic gene cluster. The identification of the cluster and bioinformatic prediction of the stereoselectivity of the embedded reductive domains within the modular type I polyketide synthase reinforced the NMR and computational stereochemical assignments for the co-isolates, particularly the stereochemically complex linear verrucosins ( and ).