γ-Butyrolactones and γ-butenolides as autoregulatory systems: key mediators of intraspecific, interspecific, and interkingdom communication in Streptomyces.

Streptomyces represent a phylogenetically coherent group of aerobic, Gram-positive, high-GC-content bacteria occupying diverse terrestrial and aquatic environments. They are renowned for their exceptional capacity to biosynthesize structurally diverse secondary metabolites, many of which serve as clinically essential antibiotics, antifungals, immunosuppressants, and anticancer agents, with broad applications in pharmaceuticals, agriculture, food, and industrial biotechnology. Quorum sensing (QS) represents a fundamental regulatory paradigm governing both intraspecies coordination and interspecies crosstalk in Streptomyces. Within this framework, gamma-butyrolactones (GBLs) and gamma-butenolides (GBNs) function as structurally analogous, receptor-specific signaling molecules that autoregulate antibiotic biosynthesis, morphological differentiation, and stress adaptation. However, despite growing insights into their intraspecies functions, the ecological range, molecular determinants, and functional outcomes of GBL- and GBN-mediated interspecies communication remain largely underexplored. This review summarizes recent advances in the chemical diversity and regulatory mechanisms of microbial GBLs and GBNs. Based on current empirical evidence, we categorize their interspecies communication functions into four distinct themes: experimentally validated ligand-receptor pairs, exogenous compound-mediated receptor responses, extract- or coculture-mediated complementation, and Streptomyces-fungi communication hypotheses. Furthermore, we propose a forward-looking research agenda integrating multi-omics, synthetic biology, and microbial ecology to decipher the mechanistic foundation of interspecies QS networks-ultimately facilitating the rational activation of silent biosynthetic gene clusters, the discovery of novel bioactive natural products, and the mitigation of antimicrobial resistance.