Shandong Provincial Animal and Poultry Green Health Products Creation Engineering Laboratory, Institute of Poultry Science, Shandong Academy of Agricultural Science, Jinan, 250100, Shandong, China.
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
Eur J Med Chem. 2023 May 5;251:115269. doi: 10.1016/j.ejmech.2023.115269. Epub 2023 Mar 12.
A series of pyridinium cation-substituted pleuromutilin analogues were designed, synthesized and evaluated for their antibacterial activities in vitro and in vivo. Most derivatives showed potent antibacterial activities, especially e4 that displayed the highest antibacterial activity against multi-drug resistant bacteria and was subjected to time-kill kinetics, resistance studies, cytotoxicity and molecular docking assays. Molecular docking results, scanning electron microscopy and o-nitrophenyl-β-galactopyranoside tests showed that e4 not only inhibited bacterial protein synthesis but also disrupted bacterial cell walls. Compound e4 showed an ED of 5.68 mg/kg against multi-drug resistant Staphylococcus aureus in infected mice model. In in vivo and in vitro toxicity tests, e4 showed low toxic effects with an LD of 879 mg/kg to mice. These results suggest that compound e4 may be considered as a new therapeutic candidate for bacterial infections.
一系列吡啶鎓阳离子取代的截短侧耳素类似物被设计、合成并评估了它们的体外和体内抗菌活性。大多数衍生物表现出很强的抗菌活性，特别是 e4，对多药耐药菌表现出最高的抗菌活性，并进行了时间杀伤动力学、耐药性研究、细胞毒性和分子对接试验。分子对接结果、扫描电子显微镜和邻硝基苯-β-半乳糖苷试验表明，e4 不仅抑制细菌蛋白质合成，还破坏细菌细胞壁。化合物 e4 在感染小鼠模型中对多药耐药金黄色葡萄球菌的 ED 为 5.68mg/kg。在体内和体外毒性试验中，e4 对小鼠的 LD 为 879mg/kg，毒性作用较低。这些结果表明，化合物 e4 可能被认为是治疗细菌感染的一种新的候选药物。
