Extending the Metabolite Diversity of the Endophyte .

Fungi are one of the most prolific sources of microbial secondary metabolites. The production of new metabolites can be achieved using multiple fermentation conditions and by adding small-molecule effectors, including epigenetic modifiers. In the framework of our Natural Product screening programme targeting the discovery of new antimicrobial compounds, we applied multiple fermentation conditions and adsorptive polymeric resins on a large collection of fungal endophytes, to increase and stimulate their fungal secondary metabolite production. During this work the endophytic fungus CF-090383 showed antimicrobial activity only when grown in presence of adsorptive polymeric resins. In addition, seven epigenetic modifiers were added to fermentations of this endophytic fungus, in an attempt to activate its cryptic pathways as well as to analyse the metabolites produced under these conditions. was seen to produce three different mycotoxin dendrodolides when the epigenetic modifiers 5-azacytidine and valproic acid were added to the fermentations, and these compounds were further characterized. However, the fungus produced the fatty acid synthesis inhibitor cerulenin, a molecule not previously described to be produced by this fungal species, only when cultivated in presence of the XAD-16 resin. We have found that the addition of XAD-16 resin resulted in four-fold higher titers in the production of cerulenin when compared to the best production conditions described in literature for the original fungal producer strain, , in a zeolite-based fermentation, used as an ammonium ion-trapping agent. The production of cerulenin by this strain of , represents an alternative source for the improved production of cerulenin with better yields.