Rethinking Microbial Chemical Ecology: Secondary Metabolites as Concentration-Dependent Signaling Hubs with Implications for Anti-Virulence Intervention.

Microorganisms construct complex social communities through the exchange and interaction of chemical substances. Traditional research has typically drawn a strict distinction between quorum-sensing (QS) signaling molecules and cytotoxic secondary metabolites; however, this simplistic classification limits our in-depth understanding of microbial chemical ecology and complex collective behavior. Recent studies have shown that many secondary metabolites exhibit dual functions, acting as signaling molecules that facilitate information exchange at low concentrations. This paper proposes an integrated signaling network framework that views secondary metabolites as key nodes linking microbial collective behavior and environmental adaptation. We explore how this network mechanism overcomes the limitations of linear signaling models, thereby elucidating how microorganisms balance cell growth and metabolite synthesis in dynamic environments. We also introduce emerging spatial omics and synthetic biology tools, which hold great potential for precisely deciphering complex chemical signaling networks at the microscopic scale. Translating these mechanisms into technological applications could enable dynamic, autonomous control of bacterial metabolism in industrial biotechnology, significantly enhancing the yield of target products. Finally, we emphasize the critical importance of reframing chemical ecology as a dynamic signaling network. This shift in ecological and evolutionary perspective not only provides novel intervention pathways based on network decoupling to address the increasingly severe crisis of antibiotic resistance (AMR) but also establishes a theoretical foundation for host microbiome regulation, environmental bioremediation, and industrial multi-strain collaborative engineering.