靶向ThyA：5-FU通过LuxS/AI-2群体感应系统抑制猪链球菌生物被膜形成和毒力的机制研究

doi:10.1016/j.jia.2024.07.007

Journal of Integrative Agriculture ›› 2026, Vol. 25 ›› Issue (6): 2510-2522.DOI: 10.1016/j.jia.2024.07.007

靶向ThyA：5-FU通过LuxS/AI-2群体感应系统抑制猪链球菌生物被膜形成和毒力的机制研究

收稿日期:2024-03-21 修回日期:2024-07-08 接受日期:2024-05-10 出版日期:2026-06-20 发布日期:2026-05-06

Targeting ThyA: Investigating the mechanisms of 5-FU-induced inhibition of biofilm formation and virulence in Streptococcus suis through LuxS/AI-2 quorum sensing

Jing Zuo^1*, Yingying Quan^1*, Yue Li¹, Dong Song¹, Jinpeng Li³, Yuxin Wang¹,Li Yi^2#, Yang Wang^1#

¹ College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China
² College of Life Science, Luoyang Normal University, Luoyang 471023, China
³ Animal Disease Prevention and Green Development Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, Chengdu 610000, China

Received:2024-03-21 Revised:2024-07-08 Accepted:2024-05-10 Online:2026-06-20 Published:2026-05-06
About author:#Correspondence Yang Wang, E-mail: wangyocean@163.com; Li Yi, E-mail: lilili123168@163.com * These authors contributed equally to this study.
Supported by:
This work was supported by the National Natural Science Foundation of China (32172852), the Excellent Youth Foundation of Henan Scientific Committee, China (222300420005), the Henan Provincial Science and Technology Research Project, China (232102110095), the Program for Innovative Research Team (in Science and Technology) in University of Henan Province, China (24IRTSTHN033) and the Key Scientific Research Projects of Universities in Henan Province, China (24A230013).

摘要/Abstract

摘要：

【背景】猪链球菌是一种重要的人畜共患病原体，影响人类和猪的健康，并引起严重的公共卫生问题。猪链球菌的致病性与其形成生物被膜和表达毒力因子的能力密切相关，这些毒力因子受LuxS/AI-2群体感应系统的调节。【目的】通过测定5-氟尿嘧啶（5-FU）对猪链球菌生物被膜形成和毒力的抑制效果，分析5-FU在LuxS/AI-2群体感应系统中的作用以及与thyA的关系，为猪链球菌潜在治疗靶点提供新的见解，并为开发有效的抗猪链球菌药物提供理论依据。【方法】首先通过生物被膜抑制试验、SEM和TEM观察、EPS和CPS测定、qRT-PCR、大蜡螟幼虫感染试验、细胞黏附和侵入试验对猪链球菌生物被膜和毒力进行测定，接着通过AI-2信号分子检测、分子对接、qRT-PCR、WB等试验确定5-FU对猪链球菌生物被膜和毒力的抑制机制，最后通过小鼠实验评估5-FU的体内治疗效果。【结果】5-FU处理后荚膜多糖和胞外多糖的含量显著减少，阐明了生物被膜弱化的潜在机制。此外，5-FU能够下调毒力特征，并降低猪链球菌粘附宿主细胞和逃避吞噬的能力。进一步研究确定5-FU可以通过LuxS/AI-2群体感应系统影响猪链球菌的生物被膜形成和毒力。虚拟分子对接和基因敲除实验证明5-FU通过靶向胸苷酸合酶调控基因thyA调节LuxS/AI-2群体感应系统。体内实验进一步验证了5-FU的治疗潜力，在小鼠模型中显示出细菌负荷的显著减少和组织损伤的减轻。【结论】5-FU通过thyA影响猪链球菌的LuxS/AI-2群体感应系统，从而降低生物被膜形成和毒力，进而导致致病性降低。【创新性】5-FU可以有效控制猪链球菌感染，并可用于指导新型抗群体感应药物的开发。

Abstract:

Streptococcus suis is a significant zoonotic agent affecting both human and pig health and poses a substantial public health concern. The pathogenicity of S. suis is intricately linked to its ability to form biofilms and express virulence factors, which are regulated by the LuxS/AI-2 quorum sensing (QS) system. Herein, we uncover a novel therapeutic avenue by demonstrating that 5-fluorouracil (5-FU), an FDA-approved anti-cancer agent, effectively mitigates biofilm formation and attenuates the virulence of S. suis. Mechanistically, we observe a significant reduction in capsular polysaccharide and extracellular polysaccharide production upon 5-FU treatment, elucidating a potential mechanism for biofilm weakening. Additionally, 5-FU down-regulates virulence traits, diminishing S. suis's ability to adhere to host cells and evade phagocytosis. Crucially, our study identifies the thymidylate synthase regulatory gene thyA as a key mediator of 5-FU's effects on the LuxS/AI-2 QS system. Virtual molecular docking and gene knockout experiments provide compelling evidence that 5-FU modulates the LuxS/AI-2 QS system by targeting thyA. In vivo experiments further validate the therapeutic potential of 5-FU, showcasing a significant reduction in bacterial load and mitigation of tissue damage in a mouse model. In conclusion, our investigation unveils 5-FU as a potent disruptor of S. suis's biofilm formation and virulence, offering a promising avenue for the control of this devastating pathogen.

Key words: Streptococcus suis , 5-fluorouracil , LuxS/AI-2 quorum sensing system , Anti-biofilm , thyA

Jing Zuo, Yingying Quan, Yue Li, Dong Song, Jinpeng Li, Yuxin Wang, Li Yi, Yang Wang. 靶向ThyA：5-FU通过LuxS/AI-2群体感应系统抑制猪链球菌生物被膜形成和毒力的机制研究[J]. Journal of Integrative Agriculture, 2026, 25(6): 2510-2522.

Jing Zuo, Yingying Quan, Yue Li, Dong Song, Jinpeng Li, Yuxin Wang, Li Yi, Yang Wang. Targeting ThyA: Investigating the mechanisms of 5-FU-induced inhibition of biofilm formation and virulence in Streptococcus suis through LuxS/AI-2 quorum sensing[J]. Journal of Integrative Agriculture, 2026, 25(6): 2510-2522.

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靶向ThyA：5-FU通过LuxS/AI-2群体感应系统抑制猪链球菌生物被膜形成和毒力的机制研究

Targeting ThyA: Investigating the mechanisms of 5-FU-induced inhibition of biofilm formation and virulence in Streptococcus suis through LuxS/AI-2 quorum sensing

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