Zhao Yanxiao, Dai Enhui, Zhang Mentao, Wu Yifan, Sun Dongjie, Ding Jiabo
Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China.
College of Veterinary Medicine, Shandong Agricultural University, Taian, China.
FASEB J. 2025 Sep 30;39(18):e71074. doi: 10.1096/fj.202500634RR.
Liquid-liquid phase separation (LLPS) has emerged as a fundamental regulatory mechanism in bacterial physiology, orchestrating essential cellular processes including gene expression, stress responses, metabolic homeostasis, and biofilm formation. This phenomenon is driven by intrinsically disordered regions (IDRs), multivalent interactions between modular domains, and dynamic protein-nucleic acid associations, with precise modulation by environmental parameters such as temperature, ionic strength, and post-translational modifications (PTMs). The resulting functional condensates confer enhanced environmental adaptability and contribute to antibiotic resistance mechanisms in bacterial populations. These assemblies further impact host-pathogen interactions through modulation of virulence factor expression and immune evasion strategies, thereby complicating infection management. This comprehensive review systematically examines the molecular mechanisms driving LLPS, its dynamic regulatory networks, and physiological functions in bacteria. We evaluate the therapeutic potential of targeting LLPS pathways for antimicrobial development, with particular emphasis on antibiotic resistance regulation and intestinal commensal colonization. Future research should elucidate the mechanistic roles of LLPS-associated biomacromolecules in bacterial physiology, characterize their assembly and disassembly dynamics, and explore their therapeutic applications to establish a theoretical foundation for innovative antimicrobial strategies.
液-液相分离（LLPS）已成为细菌生理学中的一种基本调节机制，协调包括基因表达、应激反应、代谢稳态和生物膜形成在内的重要细胞过程。这种现象由内在无序区域（IDR）、模块化结构域之间的多价相互作用以及动态的蛋白质-核酸相互作用驱动，并受到温度、离子强度和翻译后修饰（PTM）等环境参数的精确调节。由此产生的功能性凝聚物赋予细菌群体更强的环境适应性，并有助于其抗生素抗性机制。这些聚集体还通过调节毒力因子表达和免疫逃避策略进一步影响宿主-病原体相互作用，从而使感染管理变得复杂。这篇综述系统地研究了驱动LLPS的分子机制、其动态调节网络以及在细菌中的生理功能。我们评估了针对LLPS途径进行抗菌药物开发的治疗潜力，特别强调了抗生素抗性调节和肠道共生菌定植。未来的研究应阐明LLPS相关生物大分子在细菌生理学中的作用机制，表征它们的组装和解聚动力学，并探索它们的治疗应用，为创新抗菌策略奠定理论基础。
