Natural products, which can be isolated from living organisms worldwide, have played a pivotal role in drug discovery since ancient times. However, it has become more challenging to identify a structurally novel molecule with promising biological activity for pharmaceutical development, mainly due to the limited methodologies for their acquisition. In this review, we summarize our recent studies that activate the biosynthetic potential of filamentous fungi by genetic engineering to harness the metabolic flow for the efficient production of unprecedented natural products. The recent revolution in genome sequencing technology enables the accumulation of vast amounts of information on biosynthetic genes, the blueprint of the molecular construction. Utilizing the established heterologous expression system, activation of the pathway-specific transcription factor coupled with a knockout strategy, and manipulating the global regulatory gene, the biosynthetic genes were exploited to activate biosynthetic pathways and decipher the encoded enzyme functions. We show that this methodology was beneficial for acquiring fungal treasures for drug discovery. These studies also enabled the investigation of the molecular function of natural products in fungal development.

自古以来，可以从全世界的活生物体中分离出来的天然产物在药物发现中起着举足轻重的作用。但是，鉴定具有新的生物学活性的结构新颖的分子用于药物开发已变得更具挑战性，这主要是由于它们的获取方法有限。在这篇综述中，我们总结了我们最近的研究，这些研究通过基因工程激活丝状真菌的生物合成潜能，以利用代谢流有效生产前所未有的天然产物。基因组测序技术的最新革命使得能够在生物合成基因上积累大量信息，这是分子构建的蓝图。利用已建立的异源表达系统，途径特异性转录因子的激活与敲除策略结合，并操纵全局调节基因，利用生物合成基因来激活生物合成途径并破译编码的酶功能。我们表明，这种方法学对于获取用于药物发现的真菌宝藏是有益的。这些研究还使人们能够研究天然产物在真菌发育中的分子功能。