Fisetin Lowers Streptococcus suis serotype 2 Pathogenicity in Mice by Inhibiting the Hemolytic Activity of Suilysin

Zhang, Yanyan; Zong, Bingbing; Wang, Xiangru; Zhu, Yongwei; Hu, Linlin; Li, Pei; Zhang, Anding; Chen, Huanchun; Liu, Manli; Tan, Chen

doi:10.3389/fmicb.2018.01723

Cited by 22 publications

(23 citation statements)

References 59 publications

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“…The results showed that apigenin significantly inhibited the production of TNF-α, IL-1β, and IL-6 in the supernatant of J774 cells infected with SS2 in a dose-dependent manner. In addition, apigenin in combination with the first-line drug ampicillin decreased the levels of blood biochemical markers (ALT, AST, CK) and the bacterial load in the tissues of the mice infected with SS2 strain SC19, which contributed to the higher survival rate of infected mice when compared with the infected mice treated with the single anti-hemolysin compound fisetin in our study [ 11 ]. More importantly, the values of transaminases in infected mice were indicative of improvements in liver levels, which also suggested that apigenin may have an important hepato-reparative or hepato-protective effect.…”

Section: Discussionmentioning

confidence: 86%

“…SLY was reported to lyse red blood cells to release hemoglobin along with S. suis cell wall components to increase the levels of proinflammatory mediators in vivo [ 9 ]. In some previous studies, the virulence of SS2 was reduced by flavonoids, including apigenin and fisetin, which can weaken the pathogenicity of SS2 by inhibiting the hemolytic activity of SLY [ 10 , 11 , 12 ]. S. suis with high levels of SLY is more likely to cause mortality in infected models when compared with nonvirulent strains, indicating that the pathogenicity of S. suis can be enhanced by increasing the production of SLY [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Apigenin and Ampicillin as Combined Strategy to Treat Severe Streptococcus suis Infection

Lü

Wang

et al. 2021

Molecules

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As an important zoonotic pathogen, Streptococcus suis (S. suis) can cause a variety of diseases both in human and animals, especially Streptococcal toxic shock-like syndrome (STSLS), which commonly appears in severe S. suis infection. STSLS is often accompanied by excessive production of inflammatory cytokines, which is the main cause of host death. Therefore, it is urgent to find a new strategy to relieve the damage caused by STSLS. In this study, we found, for the first time, that apigenin, as a flavonoid compound, could combine with ampicillin to treat severe S. suis infection. Studies found that apigenin did not affect the growth of S. suis and the secretion of suilysin (SLY), but it could significantly inhibit the hemolytic activity of SLY by directly binding to SLY and destroying its secondary structure. In cell assays, apigenin was found to have no significant toxic effects on effective concentrations, and have a good protective effect on S. suis-infected cells. More importantly, compared with the survival rate of S. suis-infected mice treated with only ampicillin, the survival rate of apigenin combined with an ampicillin-treated group significantly increased to 80%. In conclusion, all results indicate that apigenin in combination with conventional antibiotics can be a potential strategy for treating severe S. suis infection.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Apigenin and Ampicillin as Combined Strategy to Treat Severe Streptococcus suis Infection

Lü

Wang

et al. 2021

Molecules

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“…At the end of the experiment, all the mice were euthanized by CO 2 inhalation. Cytokines were quantified using a sensitive platform based on electrochemical luminescence (Quickplex, Meso-Scale Discovery ® , Kenilworth, MD, USA) [ 42 ]. To assess the pathological changes caused by bacteria, the left lobe of each mouse lung was fixed in 4% paraformaldehyde for pathological examination.…”

Section: Methodsmentioning

confidence: 99%

Auranofin Has Advantages over First-Line Drugs in the Treatment of Severe Streptococcus suis Infections

Lü

Zhu

et al. 2020

Antibiotics

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Streptococcal toxic shock-like syndrome (STSLS) likely occurs when an individual is infected with the Streptococcus suis (S. suis) epidemic strain and is characterized by a cytokine storm, multiple organ dysfunction syndrome (MODS) and a high incidence of mortality despite adequate treatment. A number of antibiotics exhibit excellent bactericidal effects in vivo, such as fluoroquinolones, aminoglycosides (gentamicin) and β-lactams (penicillin G, ceftiofur, or amoxicillin), but are less effective for treating STSLS. Therefore, there is an urgent need to identify new compounds that can reduce the damage caused by STSLS. In the present study, we identified auranofin, an orally bioavailable FDA-approved anti-rheumatic drug as a candidate repurposed drug to treat severe S. suis infections. Our results showed that auranofin can bind to the functional domain of bacterial thioredoxin reductase, decreasing the reducing redox-responsive capacity of target bacteria and allowing for the killing of S. suis cells. We also observed that auranofin has antibacterial activity against other gram-positive bacteria, such as multidrug resistant Streptococcus pneumoniae (MDRSP), Streptococcus agalactiae, and vancomycin-resistant strains of Staphylococcus aureus. Additionally, auranofin is capable of eradicating intracellular S.suis present inside infected macrophage cells. Mouse model experimental results showed that auranofin could effectively reduce the mortality of mice infected with S. suis. Compared to the ampicillin treatment group, the survival rate of mice in the auranofin treatment group in severely infected model mice was significantly improved. These results suggest that auranofin has the potential for use as an effective antibiotic against S. suis.

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“…inoculated with PCN033 and mutant ΔvgrG1Δ0248ΔvgrG2Δ1588 at approximate 1 × 10 6 CFU. Mice were monitored for 336 hours (14 days) and survival rates were recorded as described in a previous study [92]. Five-week-old female BALB/c mice used for bacteria colonization were randomly divided into groups of five and were intravenously (i.v.)…”

Section: Animal Experimentsmentioning

confidence: 99%

Characterization of multiple type-VI secretion system (T6SS) VgrG proteins in the pathogenicity and antibacterial activity of porcine extra-intestinal pathogenic Escherichia coli

et al. 2019

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Porcine extra-intestinal pathogenic Escherichia coli (ExPEC) causes great economic losses to the pig industry and poses a serious threat to public health worldwide. Some secreted virulence factors have been reported to be involved in the pathogenicity of the infection caused by ExPEC. Type-VI secretion system (T6SS) is discovered in many Gram-negative bacteria and contributes to the virulence of pathogenic bacteria. Valine-glycine repeat protein G (VgrG) has been reported as an important component of the functional T6SS. In our previous studies, a functional T6SS was identified in porcine ExPEC strain PCN033. Further analysis of the PCN033 genome identified two putative vgrGs genes (vgrG1 and 0248) located inside T6SS cluster and another two (vgrG2 and 1588) outside it. This study determined the function of the four putative VgrG proteins by constructing a series of mutants and complemented strains. In vitro, the VgrG1 protein was observed to be involved in the antibacterial ability and the interactions with cells. The animal model experiment showed that the deletion of vgrG1 significantly led to the decrease in the multiplication capacity of PCN033. However, the deletion of 0248 and/or the deletion of vgrG2 and 1588 had no effect on the pathogenicity of PCN033. The study of four putative VgrGs in PCN033 indicated that only VgrG1 plays an important role in the interaction between PCN033 and other bacteria or host cells. This study can provide a novel perspective to the pathogenesis of PCN033 and lay the foundation for discovering potential T6SS effectors.

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Fisetin Lowers Streptococcus suis serotype 2 Pathogenicity in Mice by Inhibiting the Hemolytic Activity of Suilysin

Cited by 22 publications

References 59 publications

Apigenin and Ampicillin as Combined Strategy to Treat Severe Streptococcus suis Infection

Apigenin and Ampicillin as Combined Strategy to Treat Severe Streptococcus suis Infection

Auranofin Has Advantages over First-Line Drugs in the Treatment of Severe Streptococcus suis Infections

Characterization of multiple type-VI secretion system (T6SS) VgrG proteins in the pathogenicity and antibacterial activity of porcine extra-intestinal pathogenic Escherichia coli

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