耐甲氧西林金黄色葡萄球菌(MRSA),生物膜,和持久性是导致复发性和顽固性植入物感染的三个主要因素。尽管抗生素在临床上仍然是慢性植入物感染的主要治疗方法,只有少数药物有效清除持久性和形成的生物膜。这里,非洛地平,二氢吡啶类钙通道阻滞剂,首次报道对MRSA有抗菌作用,生物膜,和坚持。即使在连续暴露于亚致死浓度的非洛地平之后,细菌不太可能产生抗药性。此外,低剂量的非洛地平通过抑制与氨基糖苷抗性(aacA-aphD)相关的蛋白质的表达来增强庆大霉素的抗菌活性。接下来,生物膜根除试验和持久性杀灭试验表明,非洛地平对形成的生物膜和持久性具有优异的杀菌作用。此外,蛋白质分析的结果,定量代谢组学分析表明,非洛地平降低MRSA毒力(agrABC),生物膜形成和TCA循环。然后,分子对接显示非洛地平通过与ClpP蛋白酶的H口袋结合抑制持久性的生长,这可能导致大量的蛋白质降解。此外,小鼠感染模型提示非洛地平与庆大霉素合用减轻细菌负担和炎症反应。总之,低剂量的非洛地平可能是一种有希望的生物材料递送药物,以增强氨基糖苷类抗生素对MRSA引起的植入物感染的疗效。生物膜,和坚持。
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.