Omics Analyses of Biosynthetic Capacity and Antibacterial Activity of the Endophytic Fungus Cosmosporella sp. VM-42 from Vinca minor

Medicinal plants serve as valuable resources for the isolation of endophytic fungi. Vinca minor, has been reported to be a botanical source of important vinca alkaloids and emerges as a promising source for isolating endophytic fungi with antibacterial potential and biosynthetic capacity. In this study, we isolated one endophytic fungus from V. minor and identified it as Cosmosporella sp. VM-42. To date, relatively little is known about this fungal genus. Using a broth microdilution assay, we identified that the ethyl acetate extract of this isolate selectively inhibited Gram-positive bacteria, such as methicillin-sensitive and methicillin-resistant Staphylococcus aureus. We further sequenced and annotated its genome, which has a size of 39.07 Mb and encodes 9,842 protein-coding genes, including 415 genes for carbohydrate-active enzymes (CAZymes). Our untargeted metabolomic analysis shows that the fungus produces various secondary metabolites, including cyclodepsipeptides, dimeric naphtho-?-pyrones, and macrolactones, which are known to have antifungal and antibacterial activities. In addition, we used small-molecule epigenetic modulators to activate the expression of silent biosynthetic gene clusters to broaden the chemical profile of Cosmosporella sp. VM-42. We further isolated the most abundant compound from Cosmosporella sp. VM-42 and identified it as nectriapyrone (compound 27). This compound was shown to exhibit antibacterial activity against MSSA and MRSA strains with MIC and MBC values ranging from 125 to 62.5 µg/mL via a bactericidal mechanism. Taken together, we provide a first systematic analysis of Cosmosporella sp. VM-42, and our results shows that it is a promising source of compounds with pharmacological potential.