Study On The Antibacterial Effect Of Candesartan Cilexetil Against Staphylococcus Aureus

Objective: To explore the antibacterial effect and mechanism of antihypertensive drug candesartan cilexetil against Staphylococcus aureus.Methods: The antibacterial activity of candesartan cilexetil against S.aureus was detected by microbroth dilution method,disk diffusion method,time-kill assay,one-step and sequential resistance induction assays.The checkerboard dilution method was used to search for antibiotics with synergistic antibacterial effect and determine bactericidal effect.Crystal violet(CV)staining and XTT assay were used to explore the inhibition and eradication effects against biofilms.The effects on the structure and morphology of biofilms were further observed by confocal laser microscopy.The bactericidal effect of candesartan cilexetil against persisters were investigated by persisters killing assay and membrane permeation test.SYTOX Green,Di SC3(5),PI assay,ATP release test,scanning electron microscopy and transmission electron microscopy were used to explore the mechanism of its action.Hemolytic activity and cell cytotoxicity were measured by RBC hemolysis test and CCK-8cytotoxicity test.The antibacterial effect in vivo was evaluated by mouse skin abscess model.Results: The minimum inhibitory concentrations(MICs)and minimum bactericidal concentrations(MBCs)of candesartan cilexetil against S.aureus were 8～16 μg/m L and 16～32 μg/m L,respectively.The fractional inhibitory concentration index values(FICIs)of candesartan cilexetil combined with gentamicin or tobramycin against S.aureus was0.375,indicating synergistic bactericidal effect.In addition,candesartan cilexetil significantly prevented the formation of S.aureus biofilms,killed intractable persisters and destroyed the membrane integrity of plankton cells and persisters.Candesartan cilexetil possessed the features of limited cell cytotoxicity and low possibility of drug resistance.Finally,a mouse model of skin abscess demonstrated that candesartan cilexetil exhibited antibacterial effects in vivo.Conclusion: The membrane targeting antibacterial agent candesartan cilexetil has strong antibacterial effect in vitro and in vivo,and is a potential antibacterial agent for the treatment of resistant S.aureus infection.