Integrating Genomics and Metabolomics for the Targeted Discovery of New Cyclopeptides with Antifungal Activity from a Marine-Derived Fungus Beauveria felina

Sour rot, caused by Geotrichum citri-aurantii, is a major postharvest disease in citrus and results in significanteconomic losses. The genus Beauveria is recognized as a promisingsource of biocontrol agents for agricultural applications. Herein,we established a targeted strategy by integrating genomics and metabolomicsto accelerate the discovery of new cyclopeptides from antagonisticmetabolites produced by the marine-derived fungus Beauveriafelina SYSU-MS7908. As a result, we isolated and characterizedseven cyclopeptides, including six new molecules, isaridins I-N (1-6). Their chemical structures and conformationalanalysis were extensively elucidated using spectroscopic techniques(NMR, HRMS, and MS'MS data), modified Mosher's and Marfey'smethods, and single-crystal X-ray diffraction. Notably, isaridin K(3) contains a peptide backbone with an N-methyl-2-aminobutyric acid residue rarely found in natural cyclopeptides.Bioassays showed that compound 2 could significantlyinhibit the mycelial growth of G. citri-aurantii by destroying the cell membrane. These findings provide an effectivestrategy for searching for new fungal peptides for potential agrochemicalfungicides and also pave the way for further exploration of applicationsin agriculture, food, and medicine.