抄録
Filamentous fungi are rich sources of bioactive compounds, and therefore a huge number of studies to explore bioactive natural products from fungal secondary metabolites have been done. Recent fungal genome sequencing programs, however, have revealed that they contain a greater number of gene clusters encoding uncharacterized secondary metabolites in addition to those of natural products previously isolated from the same fungi. The silent biosynthetic genes generally remain unexpressed under a variety of laboratory culture conditions. The transcriptionally suppressed biosynthetic pathways are anticipated to be good sources of wide range of bioactive metabolites. Recently, HDACs were shown to suppress the production of secondary metabolites in Aspergillus nidulans and secondary metabolism in fungi is strongly affected by epigenetic regulation by chromatin re-modeling through chemical modifications to DNA and histone. Further evidence is that treatment of HDAC or DNA methyltransferase inhibitors with fungi induced the production of secondary metabolites. In order to maximize the opportunity for finding new bioactive compounds from the silent biosynthetic genes in fungi, we introduced this chemical epigenetic manipulation into our natural products exploitation. During screening for the fungal secondary metabolites under various inhibitor conditions, we found the remarkable change of the secondary metabolite profile in culture medium of Torrubiella luteorostrata (SBHA-1 mM) and Cordyceps indigotica (SBHA-1 mM), C. annullata (SBHA-500 μM) and Gibellula formosana (SBHA-1 mM and RG-108-1 mM) by comparison with those negative controls. After incensement, we carried out the isolation and structure elucidation of those EtOAc extracts and succeeded to obtain various new natural products. Furthermore, we found Chaetomium indicum, C. globosum, C. mollipilium, Epicoccum purpurascens showed the significant change of their secondary metabolism under the condition of SBHA 1 mM. C. mollipilium also showed the change by nicotinamide and this is the first example that an inhibitor of NAD+ dependent HDACs affected the secondary metabolism in fungi.
