title: Morin hydrate attenuates Staphylococcus aureus virulence by inhibiting the self-assembly of α-hemolysin.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  These findings suggested that morin is a promising candidate for the development of anti-virulence therapeutic agents for the treatment of Staph. aureus infections.
authors.affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Shi
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Deng
authors.forename: X
authors.initials: X
authors.lastname: Niu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005419:Flavonoids / Q000627:therapeutic use*; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000382:microbiology; D051379:Mice; D011023:Pneumonia, Staphylococcal / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity; D014774:Virulence / Q000187:drug effects; D047309:Flavones
chemical_list: D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D005419:Flavonoids; D006460:Hemolysin Proteins; C021091:staphylococcal alpha-toxin; C008548:morin; D047309:Flavones
keywords: Staphylococcus aureus; anti-virulence; morin hydrate; virulence factor; α-hemolysin