Mining Silent Biosynthetic Gene Clusters for Natural Products in Filamentous Fungi

Filamentous fungi are of great interest due to their powerful metabolic capabilities and potential to produce abundant various secondary metabolites as natural products (NPs), some of which have been developed into pharmaceuticals. Furthermore, high-throughput genome sequencing has revealed tremendous cryptic NPs underexplored. Based on the development of in silico genome mining, various techniques have been introduced to rationally modify filamentous fungi, awakening the silent biosynthetic gene clusters (BGCs) and visualizing the NPs originally cryptic. This review summarizes the key strategies and research advances in the activation of cryptic BGCs in filamentous fungi, including endogenous non-targeted activation, single-target activation and heterologous expression. It also provides a critical evaluation of these strategies and offers perspectives on the current state of research.