Development of Genetic Dereplication Strains in Aspergillus nidulans Results in the Discovery of Aspercryptin

To reduce the secondary metabolite background in Aspergillus nidulans and minimize the rediscovery of compounds and pathway intermediates, we created a “genetic dereplication” strain in which we deleted eight of the most highly expressed secondary metabolite gene clusters (more than 244,000 base pairs deleted in total). This strain allowed us to discover a novel compound that we designate aspercryptin and to propose a biosynthetic pathway for the compound. Interestingly, aspercryptin is formed from compounds produced by two separate gene clusters, one of which makes the well‐known product cichorine. This raises the exciting possibility that fungi use differential regulation of expression of secondary metabolite gene clusters to increase the diversity of metabolites they produce. Cutting through the mix: Deletion of eight of the most highly expressed secondary metabolite gene clusters in Aspergillus nidulans enabled the isolation of a new natural product, aspercryptin. This unusual product is biosynthesized by the combination of one known and one unexplored biosynthetic pathway.