New antifungal chlorinated orsellinic aldehydes from the deep-sea-derived fungus Acremonium sclerotigenum LW14

This study is led by Prof. Liu (Institute of Microbiology, Chinese Academy of Sciences). Cryptococcus gattii has garnered significant attention due to its ability to cause disease in both immunocompromised and immunocompetent individuals. Given the human health risks of C. gattii, there is an emerging need for new antifungal drugs. In this study, seven novel orsellinic aldehydes, acresorcinols A and B (1a/1b and 2a/2b) and acresorcinols C−F (3−5), were isolated from the deep-sea-derived fungus Acremonium sclerotigenum LW14.

The fungus was identified by its phylogenetic analysis based on morphological observation and LSU, SSU, ITS, and TEF 1-α sequences. Structurally, Compounds 1 and 2 exemplify the first reported chlorinated orsellinic aldehydes, characterized by a distinctive 6/5−5 tricyclic core structure with a bridged framework. Acresorcinol C (3) was a rare carbon-bridged resorcinol dimer via a methylene bridge. Their structures, including absolute configurations, were experimentally elucidated by spectroscopic analysis, NMR calculations with DP4+ and CP3 probability analysis, as well as ECD calculations. The bioassay results showed that all compounds exhibited antifungal activities against C. gattii 3271G1 at 32 μg/mL. Compounds 1−3 demonstrated antifungal activity against C. gattii 3271G1 with MIC values of 8, 16, and 16 µg/mL, respectively. Additionally, compounds 1 and 2 exhibited moderate antifungal activities against C. gattii R265, with the same MIC values of 16 µg/mL. These findings not only expanded the chemical space of the natural orsellinic aldehydes family, but also provided a new scaffold for promising drug candidates against C. gattii from the deep-sea-derived fungi.