Morin Attenuates Streptococcus suis Pathogenicity in Mice by Neutralizing Suilysin Activity

Li, Gen; Lu, Gejin; Qi, Zhimin; Li, Hongen; Wang, Lin; Wang, Yanhui; Liu, Bowen; Niu, Xiaodi; Deng, Xuming; Wang, Jianfeng

doi:10.3389/fmicb.2017.00460

Cited by 19 publications

(22 citation statements)

References 29 publications

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“…As shown in Fig. 1C, the supernatants from SS2 culture medium showed hemolysis activity, as previously reported (27). The supernatants from an SS2 and amentoflavone (8 to 32 g/ml) coculture system showed significantly lower hemolysis activity than that from SS2, suggesting that amentoflavone attenuated the hemolytic activity of SS2 culture supernatants.…”

Section: Resultssupporting

confidence: 86%

Amentoflavone Ameliorates Streptococcus suis-Induced Infection In Vitro and In Vivo

Shen

Niu

et al. 2018

Appl Environ Microbiol

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Streptococcus suis, an important zoonotic pathogen, has caused considerable economic losses in the swine industry and severe public health issues worldwide. The development of a novel effective strategy for the prevention and therapy of S. suis is urgently needed. Here, amentoflavone, a natural biflavonoid compound isolated from Chinese herbs that has negligible anti-S. suis activity, was identified as a potent antagonist of suilysin (SLY)-mediated hemolysis without interfering with the expression of SLY. Amentoflavone effectively inhibited SLY oligomerization, which is critical for its pore-forming activity. The treatment with amentoflavone reduced S. suis-induced cytotoxicity in macrophages (J774 cells). Furthermore, S. suis-infected mice that received amentoflavone exhibited lower mortality and bacterial burden. Additionally, amentoflavone significantly decreased the production of tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), and IL-6 in an S. suis-infected cell model. Analyses of signaling pathways demonstrated that amentoflavone reduced S. suisinduced inflammation in S. suis serotype 2 (SS2)-infected cells by regulating the p38, Jun N-terminal protein kinase 1 and 2 (JNK1/2), and NF-B pathways. The antivirulence and anti-inflammatory properties of amentoflavone against S. suis infection provide the possibility for future pharmaceutical application of amentoflavone in the treatment of S. suis infection. IMPORTANCEThe widespread use of antibiotics in therapy and in the prevention of Streptococcus suis infection in the swine industry raises concerns for the emergence of a resistant strain. The use of antivirulence agents has potential benefits, mainly because of the reduced selective pressure for the development of bacterial resistance. In this study, we found that amentoflavone is an effective agent against S. suis serotype 2 (SS2) infection both in vitro and in vivo. Our results demonstrated that amentoflavone is a promising anti-infective therapeutic for S. suis infections, due to its antivirulence and anti-inflammatory effects without antibacterial activity, with fewer side effects than conventional antibacterial agents.

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Section: Resultssupporting

confidence: 86%

Amentoflavone Ameliorates Streptococcus suis-Induced Infection In Vitro and In Vivo

Shen

Niu

et al. 2018

Appl Environ Microbiol

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“…Recently, several studies have reported that flavonoids including myricetin and morin hydrate can significantly weaken the virulence of SS2, and furthermore, the weakened pathogenicity of bacteria is due to the inhibition of hemolytic activity of suilysin ( Li et al, 2017 ; Niu et al, 2017 ). Fisetin also belonging to flavonoids, as a potential antimicrobial compound, has been identified ( Taechowisan et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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Streptococcus suis serotype 2 is a serious zoonotic pathogen and has attracted worldwide attention since the first human case was reported in Denmark in 1968. Some virulence factors have been reported to be involved in the pathogenesis of the infection caused by Streptococcus suis serotype 2, and then novel strategies to identify some anti-virulence compounds which can effectively inhibit the pathogenic bacterial infection have recently been reported. Suilysin is an essential virulence factor for Streptococcus suis serotype 2 since it creates pores in the target cells membranes, which aids bacterial colonization. The important role of suilysin in the virulence of Streptococcus suis serotype 2 renders it an ideal target for designing novel anti-virulence therapeutics. We find that fisetin, as a natural flavonoid, is a potent antagonist against suilysin-mediated hemolysis. The aim of this study is to evaluate the effect of fisetin on the hemolytic activity of suilysin from Streptococcus suis serotype 2. Fisetin is found to significantly inhibit the hemolytic activity of suilysin. Within the range of effective concentrations, fisetin does not influence the growth of Streptococcus suis serotype 2 and the expression of suilysin protein. In vitro, fisetin effectively inhibits the death of macrophages (J774A.1 and RAW264.7) infected with Streptococcus suis serotype 2 by weakening intracellular bacterial multiplication. Animal model experiment shows that fisetin effectively improves the survival rate of animals infected with Streptococcus suis serotype 2. Our findings suggest that fisetin could be used as an antitoxin against suilysin and be developed into a promising therapeutic candidate for treating Streptococcus suis serotype 2 infection.

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“…Therefore, studies aimed at discovering novel potent inhibitors of SLY and additional research to confirm the mechanism of interaction between SLY and its inhibitors are essential. In our previous literature, it was reported that morin, a natural compound could inhibit the haemolytic activity of SLY by restraining the transformation from the monomer form to the oligomer form based on the binding direct to the domain 2 of SLY 21 . In the present study, we observed that the natural compound myricetin (MYR) could inhibit the haemolytic activity of SLY.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the inhibition effect and mechanism of myricetin to Suilysin by molecular modeling

Niu

Sun

Wang

et al. 2017

Sci Rep

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In the present study, the inhibitory effect and mechanism of myricetin, a natural flavonoid compound, in relation to Suilysin (SLY) were investigated through molecular dynamics simulations, mutational analysis and fluorescence-quenching assays. Myricetin is a potential inhibitor that does not exhibit antimicrobial activity but has been shown to inhibit SLY cytotoxicity. Molecular dynamics simulations and mutational analysis revealed that myricetin binds directly to SLY in the gap between domains 2 and 3, an important region for oligomerization and pore formation. The results of principal component analysis (PCA) indicated that the binding of myricetin in this gap region restricts the conformational transition of SLY from a monomer to an oligomer, thereby counteracting the haemolytic activity of SLY. This mechanism was verified using a haemolysis assay. These results demonstrated that myricetin is a strong candidate as a novel therapeutic agent for the treatment of Streptococcus suis infections.

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Morin Attenuates Streptococcus suis Pathogenicity in Mice by Neutralizing Suilysin Activity

Cited by 19 publications

References 29 publications

Amentoflavone Ameliorates Streptococcus suis-Induced Infection In Vitro and In Vivo

Amentoflavone Ameliorates Streptococcus suis-Induced Infection In Vitro and In Vivo

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

Investigation of the inhibition effect and mechanism of myricetin to Suilysin by molecular modeling

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