Genome mining-driven discovery of bioactive fungal natural products

Natural products derived from fungal secondary metabolism represent a rich source of structurally diverse and biologically active molecules. However, traditional approaches to fungal natural product discovery often suffer from inefficiencies and redundancies. In the genomic era, genome mining has emerged as a powerful and sustainable alternative strategy, yet systematic exploration of fungal genomes remains challenging due to the lack of effective strategies for prioritizing biosynthetic gene clusters with distinctive biosynthetic features or predictable biological activities.

To accelerate the discovery of fungal natural products while enabling access to unusual biosynthetic mechanisms, we developed FunBGCeX, a fungal genome mining platform that detects biosynthetic proteins using a manually curated database of fungal natural product biosynthetic gene clusters (BGCs), the FunBGCs database.^1,2 FunBGCeX enables comprehensive identification of putative BGCs from fungal genomes and allows flexible extraction of clusters based on specific biosynthetic features or research interests. Notably, FunBGCeX can identify BGCs harboring putative self-resistance genes, providing a basis for resistance gene-guided genome mining and facilitating the targeted discovery of bioactive natural products with predictable modes of action. Using this strategy, we recently discovered a spirotetramate natural product, pterrespiramide A, which inhibits acetolactate synthase, thereby exhibiting antifungal and herbicidal activities.³

In this presentation, we will introduce the design and functionality of FunBGCeX and showcase representative fungal natural products and biosynthetic enzymes uncovered through its application, with a particular focus on previously undescribed bioactive molecules and their underlying biosynthetic logic.

References
1. J. Tang and Y. Matsuda, Nat. Commun., 2024, 15, 4312.
2. D. Yan and Y. Matsuda, Chem. Sci., 2024, 15, 3011-3017.
3. T. K. Chan, X. Wei, L. Ma, H. Wang, P. Liao and Y. Matsuda, J. Am. Chem. Soc., 2025, 147, 42100-42109.