Interspecific cross-talk: The catalyst driving microbial biosynthesis of secondary metabolites

Microorganisms co-exist and co-evolve in nature, forming intricate ecological communities. The interspecies cross-talk within these communities creates and sustains their great biosynthetic potential, making them an important source of natural medicines and high-value-added chemicals. However, conventional investigations into microbial metabolites are typically carried out in pure cultures, resulting in the absence of specific activating factors and consequently causing a substantial number of biosynthetic gene clusters to remain silent. This, in turn, hampers the in-depth exploration of microbial biosynthetic potential and frequently presents researchers with the challenge of rediscovering compounds. In response to this challenge, the coculture strategy has emerged to explore microbial biosynthetic capabilities and has shed light on the study of cross-talk mechanisms. These elucidated mechanisms will contribute to a better understanding of complex biosynthetic regulations and offer valuable insights to guide the mining of secondary metabolites. This review summarizes the research advances in microbial cross-talk mechanisms, with a particular focus on the mechanisms that activate the biosynthesis of secondary metabolites. Additionally, the instructive value of these mechanisms for developing strategies to activate biosynthetic pathways is discussed. Moreover, challenges and recommendations for conducting in-depth studies on the cross-talk mechanisms are presented.