Fosfomycin Protects Mice From Staphylococcus aureus Pneumonia Caused by α-Hemolysin in Extracellular Vesicles by Inhibiting MAPK-Regulated NLRP3 Inflammasomes

Frontiers in Cellular and Infection Microbiology
Yanan AnLu Yu

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...Continue Reading

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Citations

Aug 14, 2020·Diseases·Viviana Albán MMónica C Gestal
Oct 13, 2020·Nucleic Acids Research·Jing TangFeng Zhu
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Feb 6, 2021·Frontiers in Immunology·Grace R PidwillSimon J Foster
Oct 8, 2021·European Respiratory Review : an Official Journal of the European Respiratory Society·Andrea SauerChristian Bode

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Methods Mentioned

BETA
enzyme-linked immunosorbent assays
bronchoalveolar
lavage
protein assay
Scanning electron microscopy
ELISA
bronchoalveolar lavage

Software Mentioned

AUTODOCK
SPSS Statistics
MODELLER9
AMBER11
MODELLER

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