Biosynthetic investigation of isocoumarins antibiotics in Streptomyces sp. MBT76 inspired the phenylpropanoids biotransformation

Phytochemical investigation of actinomycete Streptomyces sp. MBT76 enabled discovery of a series of isocoumarin antibiotics, including 6,8-dihydroxy-3-methylisocoumarin (1), 6,8-dimethoxy-3-methylisocoumarin (2), 6,7,8-trimethoxy-3-methylisocoumarin (3), and 5,6,8-trimethoxy-3-methylisocoumarin (4). The biosynthetic investigation of two methoxylated isocoumarin analogues (3 and 4) by time-course NMR-based metabolomics approach indicated the precursor 1 went through a non-regioselective oxidation, followed by subsequent methylation in the post-PKS modification stage. Inspired by this biosynthesis pathway, plant-specific phenylpropanoids were fed to the Streptomyces sp. MBT76 to generate highly oxygenated congeners. Consequently, ferulic acid acquired another methyl group at 4-OH to afford 3,4-dimethoxycinnamic acid (5) during the microbial conversion, while sinapinic acid was metabolized into mono-benzene derivatives, such as 4-hydroxy-3,5-dimethoxy-phenol (6). More importantly, the isoflavone genistein could be biotransformed into the unprecedented 4',5,6,7,8-pentahydroxy-isoflavone (10), in addition to the dimethylated derivative 4'-hydroxy-5,7-dimethoxyisoflavone (11). The new compound 10 exhibited antimicrobial activity against both Gram-positive bacterim Staphylococcus aureus and Gram-negative bacteria Escherichia coli.

Keywords: NMR, metabolomics, isocoumarin, phenylpropanoid, biotransformation, Streptomyces