A C-terminus modification to a binding pocket-modified vancomycin introduces a quaternary ammonium salt that provides a binding pocket-modified vancomycin analog with a second mechanism of action that is independent of D-Ala-D-Ala/D-Ala-D-Lac binding. The modification disrupts cell wall integrity and induces cell wall permeability complementary to the glycopeptide inhibition of cell wall synthesis, and provides synergistic improvements in antimicrobial potency (200-fold) against vancomycin-resistant bacteria. Combining the C- terminus and binding pocket modifications with an orthogonal (4-chlorobiphenyl ) methyl addition to the vancomycin disaccharide provides even more potent antimicrobial agents whose activity can be attributed to three independent and synergistic mechanisms of action, only one of which requires D-Ala-D-Ala/D-Ala- D-Lac binding. The resulting modified vancomycins display little propensity for acquired resistance through serial exposure of vancomycin-resistant Enterococci and their durability against such challenges as well as their antimicrobial potency follow predicable trends. Methods of treatment with and compositions containing the modified vancomycins are disclosed.
一种对结合口袋改性的
万古霉素进行C-末端修饰,引入了一个季
铵盐,为结合口袋改性的
万古霉素类似物引入了第二个作用机制,与D-Ala-D-Ala/D-Ala-D-Lac结合无关。这种修饰破坏了细胞壁完整性,诱导了细胞壁通透性,与糖肽抑制细胞壁合成相辅相成,并提供了与
万古霉素耐药细菌的协同改进(提高200倍)的抗微
生物活性。将C-末端和结合口袋改性与
万古霉素二糖的一个正交(
4-氯联苯)甲基添加相结合,提供了更强效的抗微
生物剂,其活性可归因于三种独立且协同作用的机制,其中只有一种需要D-Ala-D-Ala/D-Ala-D-Lac结合。结果修饰后的
万古霉素类药物在连续暴露于
万古霉素耐药肠球菌后,几乎没有获得性耐药性的倾向,它们对抗这种挑战的耐久性以及抗微
生物活性遵循可预测的趋势。公开了使用和含有修饰后的
万古霉素的治疗方法和组合物。