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

Bioactive Materials

Bing Yue¹  Shutao Zhang²  Xinhua Qu²  Haozheng Tang²  Minqi Wang²  You Wang²  Juyang Jiao²  Weien Yuan³  Hongtao Yang⁴ 

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

关键词: Aminoglycosides;    Felodipine;    Persisters;    Methicillin-resistant Staphylococcus aureus;    Implant infection;   

DOI  :  

来源: DOAJ

【 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.

【 授权许可】

Unknown