Morin hydrate attenuates Staphylococcus aureus virulence by inhibiting the self-assembly of α-hemolysin

AimsTo investigate the mechanism by which morin hydrate inhibits the haemolytic activity of -hemolysin (Hla), a channel-forming toxin that is important for the pathogenesis of disease in experimental animals, and its therapeutic effect against Staphylococcus aureus pneumonia in a mouse model. Methods and ResultsThe results from the in vitro (haemolysis, western blot and cytotoxicity assays) and in vivo (mouse model of intranasal lung infection) experiments indicated that morin hydrate, a natural compound with little anti-Staph.aureus activity, could effectively antagonize the cytolytic activity of Hla, alleviate human lung cell injury, and protect against mortality of Staph.aureus pneumonia in a mouse model of infection. Molecular dynamics simulations, free energy calculations and mutagenesis assays were further employed to determine the catalytic mechanism of inhibition, which indicated that a direct binding of morin to the Stem' domain of Hla (residues I107 and T109) and the concomitant change in conformation led to the inhibition of the self-assembly of the heptameric transmembrane pore, thus inhibiting the biological activity of Hla for cell lysis. ConclusionsMorin inhibited Staph.aureus virulence via inhibiting the haemolytic activity of -hemolysin. Significance and Impact of the StudyThese findings suggested that morin is a promising candidate for the development of anti-virulence therapeutic agents for the treatment of Staph.aureus infections.