AUTHOR=An Yanan , Wang Yang , Zhan Jiuyu , Tang Xudong , Shen Keshu , Shen Fengge , Wang Chao , Luan Wenjing , Wang Xuefei , Wang Xueyan , Liu Mingyuan , Zheng Qingchuan , Yu Lu 

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 9 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2019.00253

DOI=10.3389/fcimb.2019.00253

ISSN=2235-2988

ABSTRACT=α-Hemolysin (Hla) is a significant virulence factor in Staphylococcus aureus (S. aureus)-infected disease such as pneumonia. So, it is necessary to choose an antibiotic that having good antibacterial activity and effect on preventing the production of Hla so that to treat S. aureus infection. In our study, we observed that Fosfomycin (FOM) inhibited the expression of Hla at sub-inhibitory concentration. Molecular dynamics demonstrated that FOM bound to the binding sites of LYS 154 and ASP 108 in the Hla, which may cause the inhibition of Hla. Furthermore, we verified staphylococcal membrane-derived vesicles (SMVs) contained Hla, and FOM treatment significantly reduced the production of SMVs and Hla. Our pharmacological inhibition analysis demonstrated that ERK and p38 activated NLRP3 inflammasome. Moreover, FOM inhibited the expression of MAPKs and NLRP3 inflammasome-related proteins in S. aureus or SMVs-infected human macrophage (MФ) 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 those of its parent strain 8325-4. And FOM significantly reduced the phosphorylation levels of ERK, P38, and the expression of NLRP3 inflammasome-related proteins. In addition, FOM also decrease the MPO activity, pulmonary vascular permeability and edema formation in lungs of mice with S. aureus pneumonia. Together, these data indicated that FOM had protective effects against S. aureus infection in vitro and in vivo via inhibiting Hla in SMVs and blocking ERK/P38-mediated NLRP3 inflammasome activation by Hla.