Recent advances in inducing endophytic fungal specialized metabolites using small molecule elicitors including epigenetic modifiers

Today when the quest of new lead molecules to supply the development pipeline is driving the course of drug discovery, endophytic fungi with their outstanding biosynthetic potential seem to be highly promising avenues for natural product scientists. However, challenges such as the production of inadequate quantities of compounds, the attenuation or loss of ability of endophytes to produce the compound of interest when grown in culture and the inability of fungal endophytes to express their full biosynthetic potential in laboratory conditions have been the major constraints. These have led to the application of small chemical elicitors that induce epigenetic changes in fungi to activate their silent gene clusters optimizing the amount of metabolites of interest or inducing the synthesis of hitherto undescribed compounds. In this respect small molecular weight compounds which are known to function as inhibitors of histone deacetylase (HDAC), DNA methyltransferase (DNMT) and proteasome have proven their efficacy in enhancing or inducing the production of specialized metabolites by fungi. Moreover, organic solvents, metals and plants extracts are also acknowledged for their ability to cause shifts in fungal metabolism. We highlight the successful studies from the past two decades reporting the ability of structurally diverse small molecular weight compounds to elicit the production of previously undescribed metabolites from endophytic fungi grown in culture. This mini review argues in favor of chemical elicitation as an effective strategy to optimize the production of fungal metabolites and invigorate the pipeline of drug discovery with new chemical entities.