Epigenetic Genome Mining of an Endophytic Fungus Leads to Pleiotropic Biosynthesis of Natural Products

摘要

The small molecule biosynthetic potential of most filamentous fungi remains largely unexplored and represents an attractive source for new compound discovery. Genome sequencing of Calcarisporium arbuscula, a mushroom endophytic fungus, revealed 68 core genes that are involved in natural products biosynthesis. This is in sharp contrast to predominant production of the ATPase inhibitors aurovertin B (>1) and D (>2). Inactivation of a histone H3 deacetylase HdaA led to pleiotropic activation and overexpression of more than 75% of the biosynthetic genes. Sampling of the overproduced compounds led to isolation of ten compounds of which four contain new structures, including the cyclic peptides arbumycin (>3) and arbumelin (>4); the diterpenoid arbuscullic acid A (>11); and a meroterpenoid arbuscullic acid B (>12). Such epigenetic modification therefore provides a rapid and global approach to mine the chemical diversity of endophytic fungi.