HEx: A heterologous expression platform for the discovery of fungal natural products

• Published in: Science advances Vol. 4; no. 4; p. eaar5459
• Main Authors: Harvey, Colin J B, Tang, Mancheng, Schlecht, Ulrich, Horecka, Joe, Fischer, Curt R, Lin, Hsiao-Ching, Li, Jian, Naughton, Brian, Cherry, James, Miranda, Molly, Li, Yong Fuga, Chu, Angela M, Hennessy, James R, Vandova, Gergana A, Inglis, Diane, Aiyar, Raeka S, Steinmetz, Lars M, Davis, Ronald W, Medema, Marnix H, Sattely, Elizabeth, Khosla, Chaitan, St Onge, Robert P, Tang, Yi, Hillenmeyer, Maureen E
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.04.2018
• Subjects: Bioinformatica; Bioinformatics; Biological Products - metabolism; Biosynthetic Pathways; EPS; Fermentation; Fungi - genetics; Fungi - metabolism; Gene Expression; Genetic Engineering - methods; High-Throughput Screening Assays; Organismal Biology; Promoter Regions, Genetic; SciAdv r-articles; Workflow
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aar5459

For decades, fungi have been a source of U.S. Food and Drug Administration-approved natural products such as penicillin, cyclosporine, and the statins. Recent breakthroughs in DNA sequencing suggest that millions of fungal species exist on Earth, with each genome encoding pathways capable of generating as many as dozens of natural products. However, the majority of encoded molecules are difficult or impossible to access because the organisms are uncultivable or the genes are transcriptionally silent. To overcome this bottleneck in natural product discovery, we developed the HEx (Heterologous EXpression) synthetic biology platform for rapid, scalable expression of fungal biosynthetic genes and their encoded metabolites in . We applied this platform to 41 fungal biosynthetic gene clusters from diverse fungal species from around the world, 22 of which produced detectable compounds. These included novel compounds with unexpected biosynthetic origins, particularly from poorly studied species. This result establishes the HEx platform for rapid discovery of natural products from any fungal species, even those that are uncultivable, and opens the door to discovery of the next generation of natural products.