Abstract:[Background] Studies about effects of epigenetic enzyme chemical inhibitors on metabolites of fungi mainly focus on new metabolites mining while content change of large number of known metabolites are less concerned. Metarhizium anisopliae is a common insecticidal fungus which can synthetize many known bioactive metabolites. Content variation of the metabolites can possibly affect the relationship between the fungus and the environment and its utilization potential.[Objective] To assess the effects of histone deacetylase and DNA methylase inhibitors on the safety and availability of metabolites of M. anisopliae. [Methods] Chemical inhibitors of epigenetic enzyme were added in medium of M. anisopliae. After a period of cultivation the metabolic changes were analyzed with high-performance liquid chromatography (HPLC) combined with high-resolution mass spectrometry (HRMS) and with some standards comparison. The effects of the inhibitors were evaluated by the bioactivities of the changed metabolites. [Results] Results of HPLC-HRMS showed that the content of 16 main metabolites of M. anisopliae changed significantly while the concentration of the inhibitors reached 500 μmol/L. The changed metabolites included destruxin A, A1, A2, B, B1, B2, E, E2, Ed, didesmethyldestruxin C, dihydrodestruxin A, desmethyldestruxin B, 12-hydroxyovalicin, subglutinol C, fungerin and ustilagic acid C. Sodium butyrate can increase 15 of the main metabolites production, and benzamide can increase 12 of the main metabolites production. Despite that SAHA can only increase 10 of the main metabolites production, some of the increased levels were much higher than the two formers. All the destruxins were decreased in the DNA methylase inhibitors treated M. anisopliae. [Conclusion] Chemical inhibitors of histone deacetylase can increase the contents of the main metabolites of M. anisopliae while inhibitors of DNA methylase can decrease all the destruxins in the fungus. Because of that all the main variated metabolites possess insecticidal, immunosuppressive, antibacterial, anti-cancer or other biological activities, the above inhibitors can strengthen or weaken the toxicity of the fungus against insects in the environment and increase or decrease metabolic utilization value of the fungus. Additionally, subglutinol C, fungerin and ustilagic acid C were identified for the first time from M. anisopliae.
