Broadening Activity of Polymyxin by Quaternary Ammonium Grafting
Broadening Activity of Polymyxin by Quaternary Ammonium Grafting
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DOI：
10.1021/acsinfecdis.0c00037
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发表时间：
2020-06-12
影响因子：
5.3
通讯作者：
Pires, Marcos M.
中科院分区：
文献类型：
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作者：
Ongwae, George M.;Morrison, Kelly R.;Pires, Marcos M.
细菌病原体继续在地球仪上造成巨大的健康负担。在这里，我们描述了一个新的系列多粘菌素为基础的代理商接枝膜活性季铵弹头联合收割机两个重要的类革兰氏阴性菌抗菌支架。目标是利用多粘菌素的外膜归巢特性将靶向季铵弹头递送到细菌病原体的表面。最有效的药物产生了新的支架，保留了靶向革兰氏阴性细菌的能力，对哺乳动物细胞的毒性有限。我们使用分子动力学方法表明，新药物保留了与脂多糖分子进行特异性相互作用的能力。值得注意的是，季铵和多粘菌素的组合扩大了对病原体金黄色葡萄球菌的活性。我们的研究结果作为一个例子，如何两个膜活性剂可以结合起来，产生一类新的支架具有强大的生物活性。
Bacterial pathogens continue to impose a tremendous health burden across the globe. Here, we describe a novel series of polymyxin-based agents grafted with membrane-active quaternary ammonium warheads to combine two important classes of Gram-negative antimicrobial scaffolds. The goal was to deliver a targeted quaternary ammonium warhead onto the surface of bacterial pathogens using the outer membrane homing properties of polymyxin. The most potent agents resulted in new scaffolds that retained the ability to target Gram-negative bacteria and had limited toxicity toward mammalian cells. We showed, using a molecular dynamics approach, that the new agents retained their ability to engage in specific interactions with lipopolysaccharide molecules. Significantly, the combination of quaternary ammonium and polymyxin widens the activity to the pathogen Staphylococcus aureus. Our results serve as an example of how two membrane-active agents can be combined to produce a class of novel scaffolds with potent biological activity.