Tackling Antibiotic Resistance: Exploring 5-Fluorouracil as a Promising Antimicrobial Strategy for the Treatment of Streptococcus suis Infection.

Streptococcus suis (S. suis) is a zoonotic pathogen with a global distribution, which causes serious diseases in both humans and animals and economic losses in the swine industry. As antibiotic resistance increases, there is an urgent imperative to explore novel antibacterial alternatives. In the present study, we selected the anticancer drug 5-fluorouracil (5-FU) approved by the Food and Drug Administration (FDA) as a candidate drug to treat S. suis infections. The results showed that various pathogens, especially S. suis, are more sensitive to 5-FU. Moreover, the cytotoxicity of 5-FU is relatively low. Extensive in vitro assays demonstrated the pronounced bacteriostatic and bactericidal efficacy of 5-FU against susceptible and multidrug-resistant S. suis strains. Its mechanisms of action include damage to the bacterial cell walls and membranes, resulting in the leakage of intracellular components, and the inhibition of thymidylate synthase (TS), leading to a depletion of deoxythymidine triphosphate (dTTP) pools, ultimately causing thymine-less death and lethal DNA damage in bacteria. Gene-knockout experiments further showed that 5-FU played a role by inhibiting the thyA gene-encoding thymidine synthase. Finally, we determined that S. suis infections can be alleviated by 5-FU in the mouse infection model. This study emphasizes the antibacterial potential of 5-FU against S. suis and provides evidence for its targeting of bacterial membrane damage and DNA damage. In summary, 5-FU can control S. suis infection and is expected to become a new alternative to antibiotics.

Antimicrobial Resistance and Biofilm Formation of Bordetella bronchiseptica in Central China, with Evidence of a Rare Heteroresistance Strain to Gentamicin.

Bordetella bronchiseptica is a significant contributor to respiratory disease in pigs, leading to substantial economic losses in the swine industry worldwide. We isolated 52 B. bronchiseptica strains from 542 samples collected from pigs with atrophic rhinitis and bronchopneumonia in central China. Multi-locus sequence typing identified two prevalent sequence types: ST6 (69.23%) and ST7 (30.77%). PCR-based detection of seven virulence genes (fhaB, prn, cyaA, dnt, bteA, fla, and bfrZ) revealed that six of these genes were present in over 90% of the isolates, with bfrZ being the exception at 59.62%. Antimicrobial susceptibility testing, performed using the K-B method, demonstrated high sensitivity to enrofloxacin, polymyxin, and doxycycline but a notable resistance to tylosin, trimethoprim, tobramycin, ciprofloxacin, and amikacin. Remarkably, 86.54% of the isolates exhibited a multidrug-resistant phenotype. Notably, we successfully screened a strain of B. bronchiseptica with a heteroresistance phenotype to gentamicin using population analysis profiling, which is a rare case. Biofilm-formation assays indicated that 96.15% of the isolates possessed biofilm-forming capabilities. These findings provide crucial insights into the prevalence of B. bronchiseptica in central China, facilitating the development of effective preventive measures to safeguard both animal and human health.

Bacterial capsules: Occurrence, mechanism, and function.

In environments characterized by extended multi-stress conditions, pathogens develop a variety of immune escape mechanisms to enhance their ability to infect the host. The capsules, polymers that bacteria secrete near their cell wall, participates in numerous bacterial life processes and plays a crucial role in resisting host immune attacks and adapting to their niche. Here, we discuss the relationship between capsules and bacterial virulence, summarizing the molecular mechanisms of capsular regulation and pathogenesis to provide new insights into the research on the pathogenesis of pathogenic bacteria.

Methyl anthranilate deteriorates biofilm structure of Streptococcus suis and antagonizes the capsular polysaccharide defence effect.

BACKGROUND: Streptococcus suis is an important zoonotic pathogen that often causes biofilm-associated infection. Bacterial biofilm-dependent infection is associated with enhanced drug resistance, making it difficult to eradicate. Novel therapeutic approaches are required urgently to treat infections associated with S. suis biofilm. This study aimed to investigate the effects and mechanisms of methyl anthranilate (MA) on S. suis biofilm. METHODS: The effect of MA on S. suis biofilm was determined using the crystal violet method, and the microstructure of the biofilm was observed by electron microscopy. The effects on capsular polysaccharides were determined using the phenol-sulphuric acid method and high-performance liquid chromatography. Adhesion and antiphagocytosis properties of S. suis were detected via cell assays. Molecular docking, molecular dynamics simulation and enzyme activity inhibition assays were used to further explore the effect of MA on AI-2 quorum sensing (QS) of S. suis. Finally, the therapeutic effect of MA was investigated using a mouse infection model. RESULTS: MA destroyed the structure of S. suis biofilm, hindered biofilm formation, and reduced the synthesis of capsular polysaccharides significantly, which further weakened the adhesion and antiphagocytosis ability of S. suis. MA had a docking effect and binding site (SER76 and ASP197) similar to S-adenosylhomocysteine (SAH). Further analysis showed that MA competitively bound 5'-methyladenosine/S-adenosine homocysteine nucleosidase with SAH to interfere with AI-2 QS. In a mouse model, MA reduced the bacterial burden and inflammatory infiltrates effectively. CONCLUSION: This study revealed the antibiofilm effects of MA, and highlighted its potential as a QS inhibitor against S. suis infection.