化学
衍生化
万古霉素
敏化
抗生素
膜透性
溶解
糖肽
药理学
糖肽抗生素
组合化学
膜
生物物理学
色谱法
生物化学
细菌
医学
高效液相色谱法
免疫学
金黄色葡萄球菌
生物
遗传学
作者
E Lei,Huanyu Tao,Jian Ku Shang,An-Shik Yang,Yu Zhou,Min Wang,Kang Wen,Yi Wang,Zhiyong Chen,Xianhui Chen,Junfeng Song,Chao Zhou,Wei Huang,Lili Xu,Dongliang Guan,Cuiyan Tan,Haoran Liu,Qingyun Cai,Kai Zhou,Justin A. Modica,Sheng‐You Huang,Wei Huang,Xinxin Feng
摘要
Gram-negative bacteria, especially the ones with multidrug resistance, post dire challenges to antibiotic treatments due to the presence of the outer membrane (OM), which blocks the entry of many antibiotics. Current solutions for such permeability issues, namely lipophilic-cationic derivatization of antibiotics and sensitization with membrane-active agents, cannot effectively potentiate the large, globular, and hydrophilic antibiotics such as vancomycin, due to ineffective disruption of the OM. Here, we present our solution for high-degree OM binding of vancomycin via a hybrid “derivatization-for-sensitization” approach, which features a combination of LPS-targeting lipo-cationic modifications on vancomycin and OM disruption activity from a sensitizing adjuvant. 106- to 107-fold potentiation of vancomycin and 20-fold increase of the sensitizer’s effectiveness were achieved with a combination of a vancomycin derivative and its sensitizer. Such potentiation is the result of direct membrane lysis through cooperative membrane binding for the sensitizer–antibiotic complex, which strongly promotes the uptake of vancomycin and adds to the extensive antiresistance effectiveness. The potential of such derivatization-for-sensitization approach was also supported by the combination’s potent in vivo antimicrobial efficacy in mouse model studies, and the expanded application of such strategy on other antibiotics and sensitizer structures.
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