Discovery of Structurally Diverse Novel Natural Products from Fungi Living in Plants or Arthropods by Using Chemical Epigenetic Method

Abstract

The epigenetic manipulation of fungal gene expression by small molecule DNA methyl transferase and/or histone deacetylase (HDAC) inhibitors influences secondary metabolism in the fungus and is an appropriate method for exploring novel fungal metabolites from cryptic biosynthetic pathways. Indeed, such chemical epigenetic method developed by us has enabled easy access for various novel skeletal natural products. However, it still remains to be investigated that what kind of fungi respond to the method well and give us structurally and biologically interesting natural products. We focused on fungi living in plants or arthropods as microbial resources for our natural product exploitation using chemical epigenetic method. When those fungi produce a variety of bioactive secondary metabolites under various stimuli derived from the interactions with their hosts, their biosynthetic gene clusters may be silenced under laboratory culture conditions. Thus, it means that they have a great potential to be a rich sources of novel natural products.

We isolated various fungi from medicinal plants and arthropods, mainly insects and spiders. The phylogenetic tree based on their gene alignment of D1/D2 region showed that the species of isolated fungi depend on the hosts, and plants and arthropods are good sources of diverse fungi. We applied the chemical epigenetic method to the isolated fungi and found that Penicillium sp. (Catharanthus roseus), Graphiopsis chlorocephala (Paeonia lactiflora) and Mycosphaerella sp. (Aloe arborescens) enhanced the accumulation of their secondary metabolites, leading to the isolation of structurally diverse novel polyketides such as a-pyrone with bicyclo[4.2.0]octadiene (1), benzophenones with chlorine atom (6, 7 and 11), and short branched fatty acid dimers with highly substituted cyclohexenedione core (12–15). We also found that some fungi isolated from arthropods showed significantly alteration of their secondary metabolite productions by HDAC inhibitor. We therefore showed that fungi living in plants and arthropods are good sources of novel natural products by applying the chemical epigenetic method.