Abstract
α-Hemolysin (Hla) is a significant virulence factor in Staphylococcus aureus (S. aureus)-caused infectious diseases such as pneumonia. Thus, to prevent the production of Hla when treating S. aureus infection, it is necessary to choose an antibiotic with good antibacterial activity and effect. In our study, we observed that Fosfomycin (FOM) at a sub-inhibitory concentration inhibited expression of Hla. Molecular dynamics demonstrated that FOM bound to the binding sites LYS 154 and ASP 108 of Hla, potentially inhibiting Hla. Furthermore, we verified that staphylococcal membrane-derived vesicles (SMVs) contain Hla and that FOM treatment significantly reduced the production of SMVs and Hla. Based on our pharmacological inhibition analysis, ERK and p38 activated NLRP3 inflammasomes. Moreover, FOM inhibited expression of MAPKs and NLRP3 inflammasome-related proteins in S. aureus as well as SMV-infected human macrophages (MΦ) and alveolar epithelial cells. In vivo, SMVs isolated from S. aureus DU1090 (an isogenic Hla deletion mutant) or the strain itself caused weaker inflammation than that of its parent strain 8325-4. FOM also significantly reduced the phosphorylation levels of ERK and P38 and expression of NLRP3 inflammasome-related proteins. In addition, FOM decreased MPO activity, pulmonary vascular permeability and edema formation in the lungs of mice with S. aureus-caused pneumonia. Taken together, these data indicate that FOM exerts protective effects against S. aureus infection in vitro and in vivo by inhibiting Hla in SMVs and blocking ERK/P38-mediated NLRP3 inflammasome activation by Hla.
Highlights
Staphylococcus aureus (S. aureus) is an opportunistic and resilient a major bacterial pathogen in humans that colonizes mucosal surfaces (Nair et al, 2014; Lehar et al, 2015)
The results showed that purified Hla and staphylococcal membrane-derived vesicles (SMVs) caused significant hemolysis and that FOM significantly inhibited hemolysis caused by purified Hla and purified SMVs (Figure 1F)
The levels of NLRP3 inflammasome-related proteins in Mφ induced only by S. aureus Hla were inhibited by FOM (Figures 4I–K and Figures S3Q–X). These results suggested that FOM could inhibit NLRP3 inflammasomes induced by S. aureus, SMVs or Hla in vitro
Summary
Staphylococcus aureus (S. aureus) is an opportunistic and resilient a major bacterial pathogen in humans that colonizes mucosal surfaces (Nair et al, 2014; Lehar et al, 2015). It can cause a significant disease burden and can grow on most tissues of the host, including the skin, nares, bones, joints, and muscles and even in the heart and lungs (Alonzo and Torres, 2014; Zhang et al, 2015). The most important S. aureus toxin is α-hemolysin (Hla), a watersoluble monomeric protein that is a cytolytic exotoxin secreted by most pathogenic strains of S. aureus and has a molecular mass of 33.2 kDa (Tanaka et al, 2011). SMVs are spherical complexes that are extracellular vesicular structures and include proteins and toxins, among other substances (Lee et al, 2009)
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