Angucystemycins, Highly Oxygenated Acetylcysteine-Angucycline Hybrid Conjugates Derived from a Soil Metagenomic Library.

Abstract

A type II polyketide biosynthetic gene cluster (agc) was identified from a soil metagenomic library. The gene cluster harbors several distinct oxidoreductase genes, suggesting that the heterologous expression of the agc gene cluster could yield novel polycyclic aromatic polyketides featuring unique redox-driven modifications. Eight angucycline derivatives were isolated from Streptomyces albus J1074 harboring the agc gene cluster, including two new S-bridged acetylcysteine-angucycline compounds, angucystemycins (1-2), a new angucycline congener, emycin H (3), along with five known analogues, rubiginone B2 (4), emycin C (5), rubiginone B1 (6), ochromycinone (7), and emycin A (8). Their structures were elucidated based on detailed High-Resolution Electrospray Ionization Mass Spectrometry and 1D and 2D NMR spectroscopy. The proposed biosynthetic pathway of angucystemycins indicated that the angucycline core and the acetylcysteine moiety are derived from the agc biosynthetic gene cluster and S. albus J1074, respectively. In addition, emycin H (3) and emycin C (5) exhibited inhibitory activity against Bacillus subtilis 168 and B. pumilus CMCC 63202. Structural analysis suggested that the saturated bond between C-5 and C-6 contributes to the activity, whereas the introduction of a C-8 O-methyl group diminishes the antimicrobial activity of the compounds of this structural class, implying a potential structure-activity relationship.