Genome-Guided Discovery of Highly Oxygenated Aromatic Polyketides, Saccharothrixins D–M, from the Rare Marine Actinomycete <i>Saccharothrix</i> sp. D09

Abstract

Angucyclines and angucyclinones are aromatic polyketides with intriguing structures and therapeutic value. Genome mining of the rare marine actinomycete <i>Saccharothrix</i> sp. D09 led to the identification of a type II polyketide synthase biosynthetic gene cluster, <i>sxn</i>, which encodes several distinct subclasses of oxidoreductases, implying that this strain has the potential to produce novel polycyclic aromatic polyketides with unusual redox modifications. The "one strain-many compounds" (OSMAC) strategy and comparative metabolite analysis facilitated the discovery of 20 angucycline derivatives from the D09 strain, including six new highly oxygenated saccharothrixins D-I (<b>1</b>-<b>6</b>), four new glycosylated saccharothrixins J-M (<b>7</b>-<b>10</b>), and 10 known analogues (<b>11</b>-<b>20</b>). Their structures were elucidated based on detailed HRESIMS, NMR spectroscopic, and X-ray crystallographic analysis. With the help of gene disruption and heterologous expression, we proposed their plausible biosynthetic pathways. In addition, compounds <b>3</b>, <b>4</b>, and <b>8</b> showed antibacterial activity against <i>Helicobacter pylori</i> with MIC values ranging from 16 to 32 μg/mL. Compound <b>3</b> also revealed anti-inflammatory activity by inhibiting the production of NO with an IC₅₀ value of 28 μM.