Genome Mining-Guided Discovery of Two New Depsides from Talaromyces sp. HDN1820200

Depsides and their derivatives are a class of polyketides predominantly found in fungal extracts. Herein, a silent nonreducing polyketide synthase (TalsA)-containing gene cluster, which was identified from the Antarctic sponge-derived fungus <i>Talaromyces</i> sp. HDN1820200, was successfully activated through heterologous expression in <i>Aspergillus nidulans</i>. This activation led to the production of two novel depsides, talaronic acid A (<b>1</b>) and B (<b>2</b>), alongside three known compounds (<b>3</b>-<b>5</b>). The further co-expression of TalsA with the decarboxylase (TalsF) demonstrated that it could convert <b>2</b> into its decarboxylated derivative <b>1</b>. The structural elucidation of these compounds was achieved using comprehensive 1D and 2D-NMR spectroscopy, which was complemented by HR-MS analysis. Talaronic acids A and B were firstly reported heterodimers of 3-methylorsellinic acid (3-MOA) and 5-methylorsellinic acid (5-MOA). All isolated compounds (<b>1</b>-<b>5</b>) were tested for their anti-inflammatory potential. Notably, compounds <b>1</b> and <b>2</b> exhibited anti-inflammatory activity comparable to that of the positive control. These results further enrich the structural class of depside natural products.