Inhibition of α-toxin production by subinhibitory concentrations of naringenin controls Staphylococcus aureus pneumonia

Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun 130062, PR China.
Fitoterapia (Impact Factor: 2.35). 02/2013; 86(1). DOI: 10.1016/j.fitote.2013.02.001
Source: PubMed


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.
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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.
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