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

AIMS

To investigate the mechanism by which morin hydrate inhibits the haemolytic activity of α-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 RESULTS

The 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.

CONCLUSIONS

Morin inhibited Staph. aureus virulence via inhibiting the haemolytic activity of α-hemolysin.

SIGNIFICANCE AND IMPACT OF THE STUDY

These findings suggested that morin is a promising candidate for the development of anti-virulence therapeutic agents for the treatment of Staph. aureus infections.