Protective Effect Of Fosfomycin On Pneumonia In Mice Infected With Staphylococcus Aureus ?-hemolysin And Its Mechanism Of Inhibition Of MAPKs-NLRP3 Activation

Fosfomycin(FOM)is a natural broad-spectrum antibiotic,which has antibacterial activity against gram-positive bacteria and gram-negative bacteria.The FOM which effect the early stage of bacterial cytoderm synthesis can destroy or change the outer structure of bacteria,and can make other drugs into the bacteria,so as to enrich the bacteria.Staphylococcus aureus(S.aureus)is a ubiquitous and highly pathogenic pathogen,which widely exists in nature.S.aureus can colonize or infect almost all tissues of the host and cause serious diseases such as pneumonia,pseudomembranous enteritis,pericarditis,hematosepsis,sepsis,etc.It can secrete a variety of toxins,and destroy the host immune system by different ways,meanwhile destroy the cell surface protein.The ?-hemolysin(?-hla)is an essential virulence factor which included in S.aureus infections,such as pneumonia.Therefore,we should choose antibiotics which have good antibacterial activity and can eliminate ?-hla to treat S.aureus infection.FOM has the antibacterial of S.aureus,so the study on the mechanism of inhibiting S.Aureus by FOM,which can established foundation for the development of new antimicrobial agents.The purpose of this study was to investigate FOM inhibits the activity of ?-hla in S.aureus,and to explore the inhibitory effect of FOM on macrophage associated inflammatory factors,and makes preliminary research of its mechanism.In this study,the antimicrobial susceptibility test,hemolytic test,Western blot,pathological analysis of tissue testing techniques for its purpose.In order to determine the specific minimum inhibitory concentration(MIC)of FOM and minimum bactericidal concentration(MBC),and to detect the effect of FOM on S.aureus ?-hla production,and the expression of FOM and S.aureus under the action of cell level pathway related protein and inflammatory protein.The results showed that FOM inhibited the expression of ERK,JNK and P38 in the MAPKs pathway of S.aureus infected THP-1 cells;down regulation the expression of NLRP3 related protein ASC,caspase-1,IL-18 and IL-1 in THP-1 cells treated with S.aureus ?-hla;ERK and P38 specific inhibitors blocked the activation of NLRP3 inflammatory bodies,and the experiments showed that ERK and P38 regulate the activation of NLRP3 by ?-hla;In the mouse model of S.aureus infection,the inflammation caused by S.aureus DU1090 was weaker than that of the 8325-4 strain,and the levels of p-ERK,p-P38,ASC,caspase-1,IL-18 and IL-1 were significantly decreased by FOM.This study showed that FOM can effectively inhibit the hemolytic activity of S.aureus ?-hla,and has a good protective effect on S.aureus infection of macrophages,its mechanism is FOM by inhibiting expression of ?-hla in vitro and in vivo mouse model,and blocking the NLRP3 inflammasome mediated ERK/P38 then the ?-hla activation pathway.