Broadening Activity of Polymyxin by Quaternary Ammonium Grafting.,ACS Infectious Diseases

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Broadening Activity of Polymyxin by Quaternary Ammonium Grafting.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2020-03-26 , DOI: 10.1021/acsinfecdis.0c00037
George M Ongwae ₁ , Kelly R Morrison ₂ , Ryan A Allen ₂ , Seonghoon Kim ₃ , Wonpil Im ₃ , William M Wuest _{2,

4} , Marcos M Pires ₁

Affiliation

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.

中文翻译：

季铵盐接枝增强多粘菌素的活性。

细菌病原体继续给全球带来巨大的健康负担。在这里，我们描述了一系列新型的基于多粘菌素的药物与膜活性季铵弹头嫁接，以结合革兰氏阴性抗菌支架的两个重要类别。目的是利用多粘菌素的外膜归巢特性将靶向的季铵盐战斗部递送到细菌病原体的表面。最有效的药物产生了新的支架，该支架保留了靶向革兰氏阴性细菌的能力，并且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，新试剂保留了它们与脂多糖分子进行特定相互作用的能力。值得注意的是，季铵盐和多粘菌素的结合扩大了对病原体的活性金黄色葡萄球菌。我们的结果作为一个例子，说明了如何将两种膜活性剂结合起来生产出一类具有强大生物活性的新型支架。

更新日期：2020-03-26

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