Combination Strategy of Genetic Dereplication and Manipulation of Epigenetic Regulators Reveals a Novel Compound from Plant Endophytic Fungus.

The strategies of genetic dereplication and manipulation of epigenetic regulators to activate the cryptic gene clusters are effective to discover natural products with novel structure in filamentous fungi. In this study, a combination of genetic dereplication (deletion of pesthetic acid biosynthetic gene, ) and manipulation of epigenetic regulators (deletion of histone methyltransferase gene and histone deacetylase gene ) was developed in plant endophytic fungus . The deletion of with and/or led to isolation of 1 novel compound, pestaloficiol X (), as well as another 11 known compounds with obvious yield changes. The proposed biosynthesis pathway of pestaloficiol X was speculated using comparative analysis of homologous biosynthetic gene clusters. Moreover, phenotypic effects on the conidial development and response to oxidative stressors in the mutants were explored. Our results revealed that the new strain with deletion of or in Δ background host can neutralise the hyperformation of conidia in the mutant, and that the Δ Δ mutant was generally not sensitive to oxidative stressors as much as the Δ Δ mutant in comparison with the single mutant Δ or the parental strains. This combinatorial approach can be applied to discover new natural products in filamentous fungi.