Integrating genomics and metabolomics to accelerate the discovery of anti-MRSA natural products from the endophytic fungus Neocucurbitaria sp. VM-36

Endophytic fungi in medicinal plants are a rich source of bioactive natural products. Herein, we performed a comprehensive genomic and metabolic analysis of an uncharacterized endophytic fungus Neocucurbitaria sp. VM-36. Whole-genome sequencing and comparative analysis of the encoded biosynthetic gene clusters with six Cucurbitariaceae strains predicted its potential to produce compounds related to griseofulvin, usnic acid, hypothemycin, and phomasetin. Untargeted metabolomics confirmed several of these predictions with the presence of phomasetin analogs and isousnic acid, and uncovered a diverse range of other secondary metabolites, including specialized lipids, amino acids, and peptides, such as cyclic hexapeptides. We successfully isolated the main compound ( 1 ), a phomasetin analog, and show that it has bactericidal activity against different methicillin-resistant and -sensitive Staphylococcus aureus strains comparable in strength to vancomycin and daptomycin. Checkerboard assays with these compounds revealed mostly indifferent interactions. These findings demonstrate the antibacterial potential of compound 1 and Neocucurbitaria sp. VM-36.