Epigenetic manipulation of a filamentous fungus by the proteasome-inhibitor bortezomib induces the production of an additional secondary metabolite

Abstract

The use of epigenetic modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, has been explored increasingly as a technique to induce the production of additional microbial secondary metabolites. The application of such molecules to microbial cultures has been shown to upregulate otherwise suppressed genes, and in several cases has led to the production of new molecular structures. In this study, the proteasome inhibitor bortezomib was used to induce the production of an additional metabolite from a filamentous fungus (Pleosporales). The induced metabolite was previously isolated from a plant, but the configuration was not assigned until now; in addition, an analogue was isolated from a degraded sample, yielding a new compound. Proteasome inhibitors have not previously been used in this application and offer an additional tool for microbial genome mining.

Eremophilane Sesquiterpenes from a Deep Marine-Derived Fungus, Aspergillus sp. SCSIOW2, Cultivated in the Presence of Epigenetic Modifying Agents

“…The other NOE correlations were almost identical with those of the A form, suggesting the same relative configurations. The 1 H-NMR integral area showed that the two distinct sets of signals can be observed in an approximately 3:5 (A:B, Figure S21) ratio in DMSO-d 6 . On standing in MeOD-d 4 , the equilibration changed to be 1:4 (A:B, Figure S27).…”

“…Thus 2 and 3 might be artificial products. 4 was found to be a mixture of two equilibrium structures in solution formed by the same acetalization reaction, the 1 H-NMR integral area showed the two distinct sets of signals can be observed in an approximately 3:5 (A:B) ratio in DMSO-d 6 and 1:4 in MeOD-d 4 . 1 contains minor impurities too.…”

“…This observation suggests that many gene clusters generally remain unexpressed under a variety of laboratory culture conditions. Epigenetic modifying agents, primarily histone-modifying and DNA methylation-modifying agents, have been introduced as promising tools for manipulating the silent fungal genes for the purpose of discovering novel structures [4][5][6]. This approach has already been successfully applied to several marine-derived fungi to discover novel natural products using chemical epigenetic modifying agents, such as the histone deacetylase inhibitors suberohydroxamic acid (SBHA) [7,8] and sodium butyrate [9] and the DNA methyltransferase inhibitor 5-azacytidine (5-AZA) [10,11].…”

Antibiotic dialogues: induction of silent biosynthetic gene clusters by exogenous small molecules

“…Oberlies and coworkers took a slightly different approach to this method, using the proteasome inhibitor bortezomib to induce a filamentous fungus to produce cryptic metabolite 11 (Fig. 1) (VanderMolen et al 2014). While mode-of-action restrictions largely limit this method's application to fungi, the McArthur group was able to apply it in Streptomyces coelicolor (Moore et al 2012).…”

“…Thus, DNMT and HDAC inhibitors serve as effective elicitors of fungal secondary metabolite. The use of proteasome inhibitors takes advantage of the same underlying mechanism in an indirect manner: proteasomes degrade many proteins, including several transcriptional regulators (VanderMolen et al 2014).…”