Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus,persisters and biofilms  

作　　者：Shutao Zhang Xinhua Qu Juyang Jiao Haozheng Tang Minqi Wang You Wang Hongtao Yang Weien Yuan Bing Yue 

机构地区：[1]Department of Bone and Joint Surgery,Department of Orthopedics,Renji Hospital,Shanghai Jiaotong University School of Medicine,China [2]School of Medical Science and Engineering,Beihang University,Beijing,100191,China [3]Engineering Research Center of Cell&Therapeutic Antibody,Ministry of Education,School of Pharmacy,Shanghai Jiao Tong University,Shanghai,200240,China

出　　处：《Bioactive Materials》2022年第8期272-289,共18页生物活性材料（英文）

基　　金：supported by the National Natural Science Foundation of China(Grant No.82172464,82172453,81972086);National Key Research and Development Project of China(Grant No.2020YFC1107500,2020YFC1107503);The Shanghai Rising-Star Program(21QA1405500);Shanghai“Rising Stars of Medical Talent”Youth Development Program(Youth Medical Talents-Specialist Program)(Grant No.2019-72);“Technology Innovation Action Plan”Key Project of Shanghai Science and Technology Commission(Grant No.19411962800);Shanghai municipal education commission-Gaofeng clinical medicine grant support(Grant No.20161423);NSFC Advancing Targeted Projects(RJTJ-JX-005,RJTJ22-RC-011).

摘　　要：Methicillin-resistant Staphylococcus aureus(MRSA),biofilms,and persisters are three major factors leading to recurrent and recalcitrant implant infections.Although antibiotics are still the primary treatment for chronic implant infections in clinical,only few drugs are effective in clearing persisters and formed biofilms.Here,felodipine,a dihydropyridine calcium channel blocker,was reported for the first time to have antibacterial effects against MRSA,biofilm,and persisters.Even after continuous exposure to sub-lethal concentrations of felodipine,bacteria are less likely to develop resistance.Besides,low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance(aacA-aphD).Next,biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters.Furthermore,the result of protein profiling,and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence(agrABC),biofilm formation and TCA cycle.Then,molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease,which could lead to substantial protein degradation.Furthermore,murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response.In conclusion,low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA,biofilm,and persisters.

关 键 词：AMINOGLYCOSIDES FELODIPINE Persisters Methicillin-resistant Staphylococcus aureus Implant infection 

分 类 号：R318[医药卫生—生物医学工程] TB3[医药卫生—基础医学]