Gene activation strategies to unlock fungal secondary metabolism and its function

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Many filamentous fungi produce secondary metabolites that are believed to have decisive roles in intra- and inter-species communication, competition for resources, or defense of a symbiotic partner. Moreover, most of them bear unique chemical structures and are often privileged with potent bioactivities and therefore are of exceptional interest for drug discovery. Besides the importance of these metabolites, it is estimated that only a small fraction of fungal secondary metabolites has been identified, and for a much smaller fraction ecological functions are well-studied. Thus, the proposed research targets gene activation strategies in order to unlock biosynthetic gene clusters, which are silent under standard laboratory conditions and to access new secondary metabolites of Ascomycetes. For this purpose, varying culture conditions and epigenetic manipulation via histone methylation inhibition will be applied. Metabolomics will meet transcriptomics to rapidly identify newly expressed metabolites and to integrate corresponding gene expression of respective biosynthetic gene clusters. Since there is a tremendous potential to discover new chemical entities within selected four fungal genomes, the goal is to determine the absolute configurations of novel metabolites and to examine their biological function by leveraging a panel of assays with a focus on antimicrobial activity.