Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, 250012, China.
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, 250012, China.
Eur J Med Chem. 2021 Oct 5;221:113480. doi: 10.1016/j.ejmech.2021.113480. Epub 2021 Apr 28.
With the increasing incidence of antibiotic resistance, new antibacterial agents having novel mechanisms of action hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Four novel series of substituted 9-arylalkyl-10-methylacridinium derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. The results demonstrated that they exhibited broad-spectrum activities with substantial efficacy against MRSA and VRE, which were superior or comparable to the berberine, sanguinarine, linezolid, ciprofloxacin and vancomycin. In particular, the most promising compound 15f showed rapid bactericidal properties, which avoid the emergence of drug resistance. However, 15f showed no inhibitory effect on Gram-negative bacteria but biofilm formation study gave possible answers. Further target identification and mechanistic studies revealed that 15f functioned as an effective FtsZ inhibitor to alter the dynamics of FtsZ self-polymerization, which resulted in termination of the cell division and caused cell death. Further cytotoxicity and animal studies demonstrated that 15f not only displayed efficacy in a murine model of bacteremia in vivo, but also no significant hemolysis to mammalian cells. Overall, this compound with novel skeleton could serve as an antibacterial lead of FtsZ inhibitor for further evaluation of drug-likeness.
随着抗生素耐药性的不断增加，我们急需具有新型作用机制的新型抗菌药物来对抗由多药耐药（MDR）病原体引起的感染性疾病。我们设计、合成了四个新系列取代的 9-芳基烷基-10-甲基吖啶鎓衍生物作为 FtsZ 抑制剂，并评估了它们对各种革兰氏阳性和革兰氏阴性细菌的抗菌活性。结果表明，它们具有广谱活性，对 MRSA 和 VRE 具有显著疗效，优于或可与小檗碱、血根碱、利奈唑胺、环丙沙星和万古霉素相媲美。特别是最有前途的化合物 15f 表现出快速杀菌特性，可以避免耐药性的出现。然而，15f 对革兰氏阴性细菌没有抑制作用，但生物膜形成研究给出了可能的答案。进一步的靶标鉴定和机制研究表明，15f 作为一种有效的 FtsZ 抑制剂，可改变 FtsZ 自聚合的动力学，从而终止细胞分裂并导致细胞死亡。进一步的细胞毒性和动物研究表明，15f 不仅在体内菌血症的小鼠模型中显示出疗效，而且对哺乳动物细胞没有明显的溶血作用。总的来说，这种具有新型骨架的化合物可以作为 FtsZ 抑制剂的抗菌先导化合物，进一步评估其成药性。
