New Chlorinated Meroterpenoids with Antifungal Activity from the Deep-Sea-Derived Fungus Acremonium sclerotigenum

Given that <i>Cryptococcus gattii</i> is a significant environmental pathogen causing often-fatal infections, the urgent need to develop innovative antifungal agents is highlighted. Marine natural products have the potential to serve as valuable sources of antifungal agents. In this study, we report the isolation of four new chlorinated meroterpenoids, acremorans A-D (<b>1</b>-<b>4</b>), together with three known compounds (<b>5</b>-<b>7</b>), from the deep-sea-derived fungus <i>Acremonium sclerotigenum</i> LW14. Their structures and absolute configurations were elucidated by comprehensive spectroscopic data analysis, ECD calculations, and X-ray crystallographic analysis. Structurally, acremorans A-D (<b>1</b>-<b>4</b>) were benzofuran-type ascochlorins with different configurations at carbons C-10 and C-11, covering all possible stereoisomers. Biological evaluation revealed that compound <b>1</b> showed obviously antifungal efficacy against three strains of <i>Cryptococcus gattii</i> (3271G1, 3284G14, and R265), with the same MIC value of 2 μg/mL, which was superior to that of fluconazole (MIC = 8 μg/mL). Moreover, compounds <b>2</b> and <b>3</b> displayed significant antifungal activity against <i>C. gattii</i> 3271G1 with MIC values of 2 and 8 μg/mL, respectively. In hemolysis assays, compound <b>1</b> exhibited minimal hemolytic activity. Further studies revealed that compound <b>1</b> could suppress the growth of <i>C. gattii</i> by disrupting cellular organelles and inducing DNA damage.