Towards the targeted activation of silent biosynthetic gene clusters by chemical elicitors

Systematic genome mining has revealed that microbes encode numerous uncharacterized secondary metabolite biosynthetic gene clusters (BGCs). The efficient and selective activation of these silent or cryptic BGCs is crucial for the high-throughput discovery of novel natural products. Recent influential studies have demonstrated that using small chemical elicitors is a practical and cost-effective method to unlock the secondary metabolic potential of microbes. However, the current approach mainly relies on high-throughput, non-targeted screening methods to discover chemical elicitors capable of activating these silent BGCs. Therefore, this study comprehensively reviews reported cases of small molecules that activate silent BGCs, covering the chemical structures of elicitors, resulting natural products, and target BGCs, thereby constructing an integrated knowledge graph. We also summarize the underlying activation mechanisms. Leveraging relationships captured in this graph, we outline directions for targeted activation of silent pathways using small molecules, thereby facilitating more efficient natural product discovery.