Antibacterial and hemolytic activities of pyridinium polymers as a function of the spatial relationship between the positive charge and the pendant alkyl tail
Antibacterial and hemolytic activities of pyridinium polymers as a function of the spatial relationship between the positive charge and the pendant alkyl tail
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DOI：
10.1002/anie.200702287
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Sen, Ayusman
中科院分区：
文献类型：
--
作者：
Sambhy, Varun;Peterson, Blake R.;Sen, Ayusman
模拟天然抗菌肽 [1] 的膜破坏特性的合成两亲性聚合物对细菌、[2-4] 真菌、[5] 和病毒显示出有效的杀菌活性。 [6]它们的合成容易、对酶降解的稳定性以及容易的化学定制使其成为各种生物医学应用的新型化学消毒剂和非浸出杀菌剂的有希望的候选者。然而，有用的杀菌活性和对哺乳动物细胞的有害毒性之间存在微妙的平衡。在此，我们报告了两亲性吡啶鎓聚合物的化学结构和抗菌与溶血特性之间的相互作用。两亲聚合物的膜破坏活性主要取决于电荷和疏水性，必须对其进行优化才能引起膜破坏。[4,7,8]之前已经报道了结构-活性关系，即烷基尾部的长度、正电荷的增加以及聚合物的整体疏水性/亲水性对膜破坏的影响 [7-14] 所有这些变量也会影响两亲聚合物的抗菌性和溶血（毒性）特性之间的平衡。一个重要但尚未探索的问题是两亲聚阳离子的活性如何随着正电荷和疏水烷基尾部的空间定位而变化。例如，如果正电荷和烷基尾位于同一中心，而不是在空间上分离，那么聚阳离子的抗菌和溶血活性是否会有所不同？我们通过比较一系列同源两亲性吡啶鎓聚合物来解决这个问题和相关问题，这些聚合物的区别仅在于正电荷和烷基尾部的空间相关性如何。我们观察到电荷和尾部的空间定位显着影响这些聚合物的毒性，并且该结果可以用作设计具有降低毒性的聚合抗菌化合物的指导原则。
Synthetic amphiphilic polymers that mimic the membranedisrupting properties of natural antimicrobial peptides [1] show potent biocidal activity towards bacteria,[2–4] fungi,[5] and viruses.[6] Their easy synthesis, stability towards enzymatic degradation, and facile chemical tailoring make them promising candidates as novel chemical disinfectants and nonleaching biocides for a variety of biomedical applications. However, there is a delicate balance between useful biocidal activity and detrimental toxicity towards mammalian cells. Herein, we report the interplay between the chemical structure and antibacterial versus hemolytic properties of amphiphilic pyridinium polymers. The membrane-disrupting activity of amphiphilic polymers is mainly dependent on the charge and hydrophobicity, which have to be optimized to cause membrane disruption.[4, 7, 8] Structure–activity relationships have previously been reported on the effect of the length of the alkyl tail, an increase in the positive charge, and the overall hydrophobicity/hydrophilicity of the polymer on the membrane-disrupting activity.[7–14] All these variables also influence the balance between the antimicrobial and the hemolytic (toxicity) properties of the amphiphilic polymers. An important, yet unexplored, question is how the activity of an amphiphilic polycation varies as a function of the spatial positioning of the positive charge and the hydrophobic alkyl tail. For example, would the antibacterial and hemolytic activity of a polycation be any different if the positive charge and the alkyl tail were on the same center, as opposed to being spatially separated? We address this and related questions by comparing series of homologous amphiphilic pyridinium polymers that differ only in how the positive charge and the alkyl tail are spatially related. We observe that the spatial positioning of the charge and tail significantly influences the toxicity of these polymers, and this result may be used as a guiding principle in the design of polymeric antimicrobial compounds with reduced toxicity.