Hubei Biopesticide Engineering Research Centre, Wuhan 430000, China.
College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430000, China.
Int J Mol Sci. 2024 Oct 28;25(21):11574. doi: 10.3390/ijms252111574.
Restoring colistin's efficacy is crucial in addressing the resistance crisis of colistin. This study utilized a high-throughput screening method to identify 43 compounds from 800 FDA-approved drugs that exhibited significant antibacterial effects when combined with colistin. Among these, cinacalcet hydrochloride (CH) was selected for its potential synergistic effect with colistin against multidrug-resistant (MDR) strains, including -positive strains. A series of experiments revealed that the combination of CH and colistin showed strong synergy, especially in -positive strains, restoring colistin sensitivity. The combination significantly inhibited bacterial growth and reduced CFU counts more effectively than either drug alone. Additionally, CH and colistin together significantly inhibited biofilm formation and eradicated existing biofilms, as visualized through confocal microscopy. Mechanistic studies showed that the combination increased bacterial membrane permeability and disrupted membrane integrity. The treatment also elevated extracellular ATP release and ROS production, indicating oxidative stress-induced bacterial death. Safety evaluations showed that the combination did not increase toxicity in host cells. Finally, animal models further validated the combination's efficacy. Overall, this study showed that the combination of colistin and CH significantly restored colistin sensitivity in -positive , revealing their synergistic antibacterial mechanism involving membrane damage and oxidative stress, with promising clinical applications.
恢复黏菌素的疗效对于应对黏菌素耐药危机至关重要。本研究利用高通量筛选方法从 800 种已获美国食品药品监督管理局批准的药物中鉴定出 43 种化合物，这些化合物与黏菌素联合使用时具有显著的抗菌作用。其中，盐酸西那卡塞 (CH) 被选中是因为其与黏菌素对包括阳性菌株在内的多药耐药 (MDR) 菌株具有潜在的协同作用。一系列实验表明，CH 和黏菌素的联合使用具有很强的协同作用，特别是在阳性菌株中，恢复了黏菌素的敏感性。与单独使用任何一种药物相比，联合用药能更有效地抑制细菌生长并减少 CFU 计数。此外，CH 和黏菌素联合使用还能显著抑制生物膜的形成并清除现有的生物膜，这可以通过共聚焦显微镜观察到。机制研究表明，联合用药增加了细菌膜的通透性并破坏了膜的完整性。该治疗还增加了细胞外 ATP 的释放和 ROS 的产生，表明氧化应激诱导的细菌死亡。安全性评估表明，联合用药不会增加宿主细胞的毒性。最后，动物模型进一步验证了联合用药的疗效。总的来说，本研究表明，黏菌素和 CH 的联合使用显著恢复了阳性菌株对黏菌素的敏感性，揭示了它们协同抗菌的机制涉及膜损伤和氧化应激，具有广阔的临床应用前景。
