Curcumin reduces the pathogenicity of Streptococcus suis serotype 2 in mice by targeting suilysin

Background: Streptococcus suis (S. suis) is a significant zoonotic pathogen, with serotype 2 (SS2) being the most prevalent. Suilysin (SLY), an essential toxin indicator for S. suis, is crucial in the infections caused by SS2. Consequently, an anti-virulence strategy targeting SLY presents a promising approach to combat SS2. Objectives: To investigate the effect of curcumin, a naturally occurring phenolic compound, on the hemolytic activity of SLY and the pathogenicity of SS2, and to assess its viability as a novel anti-virulence candidate for addressing SS2 infections. Methods: The antibacterial activity of curcumin against SS2 was assessed by determining its minimal inhibitory concentration (MIC) and monitoring bacterial growth curves. Its impact on hemolytic activity was tested using supernatants from SS2 cultures and purified recombinant SLY protein. Western blot was used to determine if curcumin affected the secretion level of SLY. The interaction between curcumin and SLY was predicted using molecular docking. Finally, the protective efficacy of curcumin was evaluated in a murine model of lethal SS2 infection. Results: Curcumin (<1,024 ?g/mL) did not inhibit SS2 growth or viability. However, it significantly and dose-dependently inhibited the hemolytic activity of both SS2 culture supernatants and purified SLY. Molecular docking predictions indicated that curcumin engaged three domains of SLY (D1, D2 and D3) simultaneously, forming five hydrogen bonds with residues ASN-50, GLN-107 and LYS-190, thereby supporting its multidomain-binding capability. Furthermore, curcumin administration significantly reduced the mortality of SS2-infected mice in vivo. Conclusion: Substantial evidence is presented demonstrating that the pathogenicity of SS2 can be effectively attenuated by curcumin via inhibition of the hemolytic activity of SLY, which supports the potential utility of curcumin as a host-directed anti-virulence agent for SS2 infections.