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

A type II polyketide biosynthetic gene cluster (<i>agc</i>) was identified from a soil metagenomic library. The gene cluster harbors several distinct oxidoreductase genes, suggesting that the heterologous expression of the <i>agc</i> gene cluster could yield novel polycyclic aromatic polyketides featuring unique redox-driven modifications. Eight angucycline derivatives were isolated from <i>Streptomyces albus</i> J1074 harboring the <i>agc</i> gene cluster, including two new S-bridged acetylcysteine-angucycline compounds, angucystemycins (<b>1</b>-<b>2</b>), a new angucycline congener, emycin H (<b>3</b>), along with five known analogues, rubiginone B2 (<b>4</b>), emycin C (<b>5</b>), rubiginone B1 (<b>6</b>), ochromycinone (<b>7</b>), and emycin A (<b>8</b>). 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 <i>agc</i> biosynthetic gene cluster and <i>S. albus</i> J1074, respectively. In addition, emycin H (<b>3</b>) and emycin C (<b>5</b>) exhibited inhibitory activity against <i>Bacillus subtilis</i> 168 and <i>B. pumilus</i> 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 <i>O</i>-methyl group diminishes the antimicrobial activity of the compounds of this structural class, implying a potential structure-activity relationship.