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 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 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.

中文翻译：

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HEx：用于发现真菌天然产物的异源表达平台。

几十年来，真菌一直是美国食品和药物管理局批准的天然产品的来源，例如青霉素，环孢菌素和他汀类药物。DNA测序的最新突破表明，地球上存在数百万种真菌，每种基因组编码的途径能够产生多达数十种天然产物。但是，大多数编码的分子很难或不可能接近，因为这些生物无法耕种或基因在转录上是沉默的。为了克服天然产物发现中的瓶颈，我们开发了HEx（异源表达）合成生物学平台，用于在酿酒酵母中快速，可扩展地表达真菌生物合成基因及其编码的代谢产物。我们将此平台应用于来自世界各地不同真菌物种的41种真菌生物合成基因簇，其中22种产生了可检测的化合物。其中包括具有意想不到的生物合成来源的新型化合物，尤其是来自研究不足的物种。这一结果为快速发现任何真菌物种（甚至是那些无法耕种的真菌物种）的天然产物建立了HEx平台，并为发现下一代天然产物打开了大门。