Induction of Diverse Cryptic Fungal Metabolites by Steroids and Channel Blockers

• Published in: Angewandte Chemie 2022-07, Vol.134 (29), p.n/a
• Main Authors: Lee, Seoung Rak, Seyedsayamdost, Mohammad R.
• Format: Article
• Language: English
• Subjects: Antibiotics; Biosynthesis; Chemical ecology; Chemistry; Cryptic Metabolites; Ecological effects; Fungi; Gene clusters; Genetic screening; Genetics; High-Throughput Elicitor Screening; Metabolites; Natural Products; Steroid hormones; Steroids
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202204519

Fungi offer a deep source of natural products but remain underutilized. Most biosynthetic gene clusters (BGCs) that can be detected are silent or “cryptic” in standard lab cultures and their products are thus not interrogated in routine screens. As genetic alterations are difficult and some strains can only be grown on agar, we have herein applied an agar‐based high‐throughput chemical genetic screen to identify inducers of fungal BGCs. Using R. solani and S. sclerotiorum as test cases, we report 13 cryptic metabolites in four compound groups, including sclerocyclane, a natural product with a novel scaffold. Steroids were the best elicitors and follow‐up studies showed that plant‐steroids trigger sclerocyclane synthesis, which shows antibiotic activity against B. plantarii, an ecological competitor of S. sclerotiorum. Our results open new paths to exploring the chemical ecology of fungal‐plant interactions and provide a genetics‐free approach for uncovering cryptic fungal metabolites. Fungi encode a diverse array of secondary metabolites that remain to be mined. The first agar‐based high‐throughput elicitor screen with two fungal strains was conducted and led to the identification of FDA‐approved drugs as strong enhancers of secondary metabolism. The elicitors enabled the discovery of 13 novel cryptic metabolites, notably sclerocyclane with an unprecedented azatropane scaffold and antimicrobial activity against an ecological competitor of fungi.