S81: Triggering cryptic natural product biosynthesis in fungi

Microorganisms produce a multitude of bioactive natural products, many of which have found application in medicine. Recent whole genome sequencing projects, however, have revealed that the number of genes encoding biosynthetic enzymes in various microorganisms clearly outnumbers the known secondary metabolites, thus suggesting that only a subset of these genes are expressed under standard culture conditions. To access this hidden reservoir of potentially bioactive natural products, it is necessary to understand the physiological conditions under which these compounds are produced, and to identify potential trigger mechanisms to induce the expression of biosynthetic genes. Using Aspergillus nidulans as a model organism, we pursued diverse strategies to elicit the formation of such cryptic secondary metabolites. By challenging the fungus through external cues and co-cultivation experiments to mimic the natural fungal environment, we were able to trigger the production of antiproliferative isoindolinone alkaloids and several highly functionalised aromatic polyketides. Modulation of global regulatory mechanisms by gene deletion experiments uncovered the biosynthesis of unique heterocyclic pigments with cytostatic properties. Our results highlight the greatly underestimated biosynthetic potential of microorganisms and point out strategies to exploit microbial chemical diversity.