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

Abstract

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.

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

“…In vitro , this study finds that fisetin efficiently inhibits the hemolytic activity of suilysin ( Figure 1C ), and that it has little antibacterial activity against SC19 at the concentrations of 32 μg/ml ( Figure 2A ). The result of our study is consistent with that of the experiment by Niu et al (2017) who reported that myricetin inhibited suilysin cytotoxicity without exhibiting antimicrobial activity. Meanwhile, Li et al (2017) reported that another flavonoid morin hydrate protects mice from SS2 infection by inhibiting the hemolytic activity of suilysin.…”

“…In addition, we found that the hemolytic activity of supernatant incubated with fisetin was inhibited ( Figure 1D ), and that there was no significant difference in suilysin expression level of SC19 with 32 μg/ml of fisetin ( Figure 2B ). Taken together, fisetin inhibits the hemolytic activity of SC19 as described by Li et al (2017) and Niu et al (2017) .…”

“…Some studies have reported that flavonoids can decrease the virulence of bacterial pathogens ( Kang et al, 2006 ; Wang et al, 2015 ; Li et al, 2017 ; Niu et al, 2017 ) by inhibiting the hemolytic activities of hemolysin. It can be concluded that the suilysin in the SC19 culture supernatant could sufficiently induce hemolysis since approximately 95% of sheep erythrocytes were lysed at the concentration of supernatant (125 μl/ml) ( Figure 1A ).…”

“…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 ).…”

Luteolin decreases the pathogenicity of Aeromonas hydrophila via inhibiting the activity of aerolysin

“…Qiu et al demonstrated that baicalin could reduce the activity of α-hemolysin of Staphylococcus aureus ( S. aureus ) through binding to α-toxin and hindering the formation of functional heptamer, which resulted in the decrease of pathogenicity of S. aureus to mice [ 39 ]. Myricetin, a natural flavonoid compound, has been reported to be a candidate for the treatment of Streptococcus suis by abolishing the activity of suilysin via inhibiting oligomer formation [ 40 ]. Lu et al found that betulin attenuated the virulence of Listeria monocytogenes in a mice infection model by suppressing the oligomerization process of listeriolysin O (LLO) [ 41 ].…”