Development of microbial chassis for production of fungal natural products

Fungal natural products (FNPs) are an important class of natural medicines. Genome sequencing has uncovered an unexpectedly large number of silent biosynthetic gene clusters (BGCs) in fungi that hold potential for FNP production. However, activating silent BGCs in native hosts is hindered by undesirable traits, such as difficulty in genetic manipulation or exhibiting extremely low metabolite titers. With the development of synthetic biology, heterologous expression systems are increasingly becoming the preferred option to overcome these limitations. In this review, we first summarize the major structural classes of FNPs and the corresponding backbone enzymes. We then evaluate the key features of various microbial chassis and strategies employed for pathway refactoring to achieve efficient heterologous expression. Furthermore, we discuss optimization strategies that enhance pathway flux toward the target product and minimize by-product formation. These methodologies are essential for advancing heterologous platforms for FNP discovery and biosynthesis. Additionally, we analyze current challenges and propose solutions to further improve microbial chassis for more effective FNP production.