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

For decades, fungi have been a source of U.S. Food and Drug Administration–approved natural productssuch 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 productdiscovery, we developed the HEx( Heterologous EXpression) synthetic biologyplatform for rapid, scalable expression of fungal biosynthetic genes and their encoded metabolites in Saccharomyces cerevisiae . 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 HExplatform for rapid discovery of natural productsfrom any fungal species, eventhose that are uncultivable, and opens the door to discovery of the next generation of natural products.