BGC heteroexpression strategy for production of novel microbial secondary metabolites

Biosynthetic gene clusters (BGCs) in microbial genomes play a crucial role in the biosynthesis of diverse secondary metabolites (SMs) with pharmaceutical potential. However, most BGCs remain silent under conventional conditions, resulting in the frequently repeated discovery of known SMs. Fortunately, in the past two decades, the heterologous expression of BGCs in genetically tractable hosts has emerged as a powerful strategy to awaken microbial metabolic pathways for making novel microbial SMs. In this review, we comprehensively delineated the development and application of this strategy, highlighting various BGC cloning and assembly techniques and their technical characteristics. We also summarized 519 novel SMs from BGC hetero-expression-derived strains and described their occurrence, bioactivity, mode of action, and biosynthetic logic. Lastly, current challenges and future perspectives for developing more efficient BGC hetero-expression strategies were discussed in this review.