Merochlorins A–D, Cyclic Meroterpenoid Antibiotics Biosynthesized in Divergent Pathways with Vanadium-Dependent Chloroperoxidases

Meroterpenoids are mixed polyketide-terpenoid natural
products
with a broad range of biological activities. Herein, we present the
structures of four new meroterpenoid antibiotics, merochlorins A–D,
produced by the marine bacterium Streptomyces sp.
strain CNH-189, which possess novel chemical skeletons unrelated to
known bacterial agents. Draft genome sequencing, mutagenesis, and
heterologous biosynthesis in the genome-minimized model actinomycete Streptomyces coelicolor provided the 57.6 kb merochlorin
gene cluster that contains two genes encoding rare bacterial vanadium-dependent
haloperoxidase (VHPO) genes. Pathway expression of two different fosmid
clones that differ largely by the presence or absence of the VHPO
gene mcl40 resulted in the differential biosynthesis
of merochlorin C, suggesting that Mcl40 catalyzes an unprecedented
15-membered chloronium-induced macrocyclization reaction converting
merochlorin D to merochlorin C.