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Exploiting Macromolecular Design To Optimize the Antibacterial Activity of Alkylated Cationic Oligomers
Biomacromolecules ( IF 6.2 ) Pub Date : 2018-10-25 00:00:00 , DOI: 10.1021/acs.biomac.8b01317
James L. Grace 1, 2 , Elena K. Schneider-Futschik 2, 3 , Alysha G. Elliott 4 , Maite Amado 4 , Nghia P. Truong 1, 2 , Matthew A. Cooper 4 , Jian Li 5 , Thomas P. Davis 1, 2, 6 , John F. Quinn 1, 2 , Tony Velkov 2, 3 , Michael R. Whittaker 1, 2
Affiliation  

There is growing interest in synthetic polymers which co-opt the structural features of naturally occurring antimicrobial peptides. However, our understanding of how macromolecular architecture affects antibacterial activity remains limited. To address this, we investigated whether varying architectures of a series of block and statistical co-oligomers influenced antibacterial and hemolytic activity. Cu(0)-mediated polymerization was used to synthesize oligomers constituting 2-(Boc-amino)ethyl acrylate units and either diethylene glycol ethyl ether acrylate (DEGEEA) or poly(ethylene glycol) methyl ether acrylate units with varying macromolecular architecture; subsequent deprotection produced primary amine functional oligomers. Further guanylation provided an additional series of antimicrobial candidates. Both chemical composition and macromolecular architecture were shown to affect antimicrobial activity. A broad spectrum antibacterial oligomer (containing guanidine moieties and DEGEEA units) was identified that possessed promising activity (MIC = 2 μg mL–1) toward both Gram-negative and Gram-positive bacteria. Bacterial membrane permeabilization was identified as an important contributor to the mechanism of action.

中文翻译:

利用高分子设计优化烷基化阳离子低聚物的抗菌活性

对合成聚合物的兴趣日益浓厚,它们共同采用天然存在的抗菌肽的结构特征。但是,我们对大分子结构如何影响抗菌活性的理解仍然有限。为了解决这个问题,我们研究了一系列嵌段和统计共聚体的不同结构是否影响了抗菌和溶血活性。使用Cu(0)介导的聚合反应合成低聚物,这些低聚物构成了丙烯酸2-(Boc-氨基)乙基酯单元和具有不同大分子结构的二乙二醇乙基丙烯酸酯(DEGEEA)或聚乙二醇甲基丙烯酸甲酯单元;随后的脱保护产生伯胺官能的低聚物。进一步的胍基化作用提供了另外一系列的抗微生物候选物。化学成分和大分子结构均显示影响抗菌活性。鉴定出具有广阔前景的广谱抗菌低聚物(包含胍基和DEGEEA单元)(MIC = 2μgmL–1)同时针对革兰氏阴性菌和革兰氏阳性菌。细菌膜通透性被确定为作用机理的重要贡献者。
更新日期:2018-10-25
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