Inhibition of α-toxin production by subinhibitory concentrations of naringenin controls Staphylococcus aureus pneumonia
ABSTRACT Staphylococcal pneumonia provoked by methicillin-resistant Staphylococcus aureus (MRSA) is a life-threatening infection in which α-toxin is an essential virulence factor. In this study, we investigate the influence of naringenin on α-toxin production and further assess its therapeutic performance in the treatment of staphylococcal pneumonia. Remarkably, the expression of α-toxin was significantly inhibited when the organism was treated with 16μg/ml of naringenin. When studied in a mouse model of S. aureus pneumonia, naringenin could attenuate the symptoms of lung injury and inflammation in infected mice. These results suggest that naringenin is a promising agent for treatment of S. aureus infection.
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ABSTRACT: Alpha-hemolysin, a secreted pore-forming toxin, plays an indispensable role in the pathogenicity of Staphylococcus aureus. In this study, the antimicrobial activity of puerarin against S. aureus was investigated; as a result, puerarin showed no influence on the growth of this organism. However, hemolysis and western blotting assays showed that puerarin concentration dependently inhibited the secretion of alpha-hemolysin at low concentrations. Real-time RT-PCR assay was further employed to evaluate the transcriptional level of hla, the gene encoding alpha-hemolysin, and RNAIII, an effector molecule of the agr system. The results indicated that the RNAIII expression and subsequent hla transcription were also inhibited by puerarin in a dose-dependent manner. Furthermore, puerarin significantly prevented human alveolar epithelial A549 cells from S. aureus-induced injury. Thereby, puerarin may be considered as a potential candidate for the development of antivirulence drugs in the treatment of S. aureus-mediated infections.Microbial drug resistance (Larchmont, N.Y.) 12/2013; DOI:10.1089/mdr.2013.0104 · 2.52 Impact Factor
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ABSTRACT: AimsTo investigate the mechanism by which morin hydrate inhibits the hemolytic 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 S. aureus pneumonia in a mouse model.Methods and ResultsThe results from the in vitro (hemolysis, 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-S. aureus activity, could effectively antagonize the cytolytic activity of Hla, alleviate human lung cell injury, and protect against mortality of S. 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 S. aureus virulence via inhibiting the hemolytic activity of α-hemolysin.Significance and Impact of StudyThese findings suggested that morin is a promising candidate for the development of anti-virulence therapeutic agents for the treatment of S. aureus infections.This article is protected by copyright. All rights reserved.Journal of Applied Microbiology 01/2015; 118(3). DOI:10.1111/jam.12743 · 2.39 Impact Factor