Genome Mining Reveals a Highly Oxidized Bacterial Perhydrophenanthrene Meroterpenoid Smelanic Acid

Bacterial perhydrophenanthrene meroterpenoids are rare natural products featuring highly oxidized 6/6/6 fused tricyclic scaffolds. Using our previously characterized non-canonical terpene cyclase AtoE as a guide, we conducted targeted genome mining and identified a cryptic biosynthetic gene cluster in Streptomyces melanosporofaciens containing SmeD, an AtoE homolog with 46.15% sequence identity. Heterologous expression of the core gene cluster in Streptomyces albus J1074 led to the production of smelanic acid (1), whose structure was elucidated by NMR spectroscopy and X-ray crystallography. Compound 1 features a perhydrophenanthrene core with a highly oxidized side chain containing both an epoxide and a glycolic acid moiety, representing a unique oxidation pattern among bacterial meroterpenoids. This work demonstrates the effectiveness of enzyme-guided genome mining for discovering structurally novel natural products and expands the chemical diversity of bacterial meroterpenoids.