Professor Wang Yang's team from Henan University of Science and Technology: 'New use of old drugs'! 5-FU precise targeted quorum sensing system, deciphering new pathogenic mechanism of Streptococcus suis

Streptococcus suis（Streptococcus suis）It is an important zoonotic pathogen that not only endangers the pig farming industry, but also threatens human health. With the intensification of antibiotic resistance, traditional "bactericidal" prevention and control are facing challenges. How to weaken their pathogenic ability without increasing resistance pressure has become a key issue that urgently needs to be addressed.

Recently, Professor Wang Yang's team from Henan University of Science and Technology completed a project titled "Targeting ThyA: Investigating the mechanisms of 5-FU-induced inhibition of biofilm formation and virulence inStreptococcus suisThrough the study of LuxS/AI-2 quorum sensingJournal of Integrative AgriculturePublished in the 6th issue of 2026 in the Journal of Agricultural Science (English), JIA.

This study proposes a novel approach to achieve precise intervention in the pathogenicity of Streptococcus suis by regulating the bacterial quorum sensing system rather than directly inhibiting its growth. Research has found that the classic anti-cancer drug 5-fluorouracil (5-FU) can significantly weaken bacterial biofilm formation and virulence expression at sub inhibitory concentrations, revealing the enormous potential of "old drugs for new use" in the field of anti infection.

Why is Streptococcus suis difficult to control? The problem lies in the biofilm

During natural infection, Streptococcus suis does not exist in the form of individual bacteria, but tends to form complex biofilms. Bacteria in the membrane are enveloped by extracellular matrix, which enhances their adaptability to environmental pressure and effectively resists the clearance of antibiotics and the host immune system, leading to recurrent and persistent infections that are difficult to cure.

Research has shown that this process is finely regulated by the LuxS/AI-2 quorum sensing system. The system achieves information exchange between bacteria by secreting and sensing the signaling molecule AI-2, thereby synergistically regulating key physiological processes such as biofilm formation, expression of virulence factors, and host adaptation. Therefore,The quorum sensing system is actually the commander of bacterial "organized warfare"Once disturbed, the overall pathogenicity of bacteria will significantly decrease.

Research reveals: 5-FU causes Streptococcus suis to 'lose tissue ability'

Based on this background, the research team turned their attention to the classic anti-cancer drug -5-FU, to explore its potential ability to regulate bacterial population behavior. Surprisingly, under conditions far below the inhibitory concentration, 5-FU was still able to significantly weaken the pathogenic behavior of Streptococcus suis.

Research has found that after treatment with 5-FU, the biofilm formed by bacteria becomes significantly loose and structurally incomplete; The synthesis of extracellular polysaccharides (EPS) and capsule polysaccharides (CPS) also significantly decreased, directly weakening the stability of the membrane. In addition, the expression of multiple key virulence related genes was downregulated, leading to a decrease in bacterial adhesion to host cells and a weakened resistance to phagocytic cells. In the infection model, there was also a clear trend of decreased virulence.

In other words, 5-FU does not "kill" bacteria, but rather causes them to "lose their ability to cooperate and attack," thereby achieving the effect of weakening pathogenicity. This strategy provides a new pathway for anti infection research that is different from traditional antibiotics.

Key breakthrough: Revealing the mechanism from "quorum sensing" to "metabolic regulation"

After clarifying that 5-FU can weaken biofilms and virulence, the study first tracked the quorum sensing signal and found that the treatment with 5-FU significantly reduced the production of AI-2 signaling molecules, indicating that it does indeed interfere with the normal function of the LuxS/AI-2 quorum sensing system.

The traditional view is that quorum sensing systems mainly rely on LuxS protein regulation, but molecular docking results show that 5-FU cannot directly and effectively bind to LuxS, suggesting that its regulatory effect may not occur at the "end" of the signaling pathway, but rather from upstream influences.

Based on this clue, the study shifted its focus upwards and identified the key gene thyA located in the upstream metabolic pathway of quorum sensing. Research has found that 5-FU indirectly downregulates luxS expression and reduces the generation of AI-2 signaling molecules by interfering with thyA mediated metabolic processes, affecting folate and methylation cycles. After thyA is knocked out, the bacterial quorum sensing ability and virulence have significantly decreased, and it is no longer sensitive to 5-FU. This result clearly indicates that thyA is a key hub connecting "metabolic regulation" and "quorum sensing", and is also the core target for the action of 5-FU.

In vivo validation: confirmation of the effect from mechanism to actual infection model

To verify the actual effect of the above mechanism in vivo, a mouse infection model was further constructed. The result is that after treatment with 5-FU, the overall infection level of mice was effectively controlled. At the same time, in strains lacking quorum sensing systems, 5-FU no longer showed significant effects, which is consistent with in vitro results. The anti infective effect depends on the regulation of the LuxS/AI-2 system.

Conclusion: 5-FU not only weakens the pathogenic ability of Streptococcus suis in vitro, but also has a clear protective effect in vivo.

Inspiration for prevention and control: future anti infection is not just about "sterilization"

This study provides important insights for the prevention and control of Streptococcus suis and other pathogens.

1. Provided a new approach of "detoxification"By interfering with the quorum sensing system, the pathogenic ability of bacteria can be weakened without significantly inhibiting their growth, which is expected to reduce the pressure of drug resistance selection.

2. Expanded the possibility of metabolic pathways as intervention targetsResearch has shown that upstream metabolic networks can also regulate bacterial population behavior, providing new directions for anti biofilm and anti toxicity strategies.

3. Verified the potential application of "old drugs for new use"As an approved drug, 5-FU has shown new value in the field of anti infection, providing a foundation for the transformation of related strategies.

This research, completed by the team of Henan University of Science and Technology, proves once again that regulation is often more effective than confrontation in complex biological systems through cross-border application of 5-FU, a new strategy from anti-cancer drugs to anti infection. This study not only reveals a new mechanism of pathogenic regulation by Streptococcus suis, but also provides a new direction for precise anti infection in the future. When we no longer just focus on "killing bacteria", but learn to "domesticate bacteria", perhaps it is the key step towards the next generation of anti infection strategies.

Professor Wang Yang from Henan University of Science and Technology and Luoyang Normal UniversityYi LiThe professor is the corresponding author of the paper and is currently a master's studentZuo JingandQuan YingyingAs a co first author. This study was supported by the National Natural Science Foundation of China, the Central Plains Science and Technology Innovation Leading Talent Fund, the Henan Province Outstanding Youth Program, the Henan Province University Science and Technology Innovation Team Program, and the Henan Province Science and Technology Research and Development Project.

Paper link: https://doi.org/10.1016/j.jia.2024.07.007    

Title:

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

Journal Name: Journal of Integrative Agriculture

DOI: 10.1016/j.jia.2024.07.007

URL: https://scholarcast.cast.org.cn/top-news/2078003906179624960