Secondary Amine Pendant β-Peptide Polymers Displaying Potent Antibacterial Activity and Promising Therapeutic Potential in Treating MRSA-Induced Wound Infections and Keratitis
Secondary Amine Pendant β-Peptide Polymers Displaying Potent Antibacterial Activity and Promising Therapeutic Potential in Treating MRSA-Induced Wound Infections and Keratitis
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DOI：
10.1021/jacs.1c10659
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发表时间：
2022-01-10
影响因子：
15
通讯作者：
Liu, Runhui
中科院分区：
文献类型：
--
作者：
Qian, Yuxin;Deng, Shuai;Liu, Runhui
近年来，人们对开发抗菌聚合物作为宿主防御肽(HPD)的合成模拟物的兴趣越来越大，以对抗耐药细菌感染。带正电的部分在确定HDP模拟物的抗菌活性和真核毒性方面是至关重要的。大多数例子利用伯胺或胍作为正电部分的来源，其灵感来自于HDP中的赖氨酸和精氨酸残基。在这里，我们探索了胺基团的变化(伯胺、仲胺或叔胺)对模拟HDP的β-肽聚合物抗菌性能的影响。我们的研究表明，作为抗菌β-肽聚合物的阳离子部分，仲铵优于伯铵或叔铵。优化的聚合物是一种含有仲氨基的均聚物，具有强大的抗菌活性和最高的选择性(低溶血和细胞毒性)。优化的聚合物对抗生素耐药细菌显示出强大的活性，在治疗MRSA引起的伤口感染和角膜炎方面具有很高的疗效，并且具有低的急性皮肤毒性和低的角膜上皮细胞毒性。这项工作表明，仲胺在抗菌聚合物的设计中可能具有广泛的用途。
Interest in developing antibacterial polymers as synthetic mimics of host defense peptides (HPDs) has accelerated in recent years to combat antibiotic-resistant bacterial infections. Positively charged moieties are critical in defining the antibacterial activity and eukaryotic toxicity of HDP mimics. Most examples have utilized primary amines or guanidines as the source of positively charged moieties, inspired by the lysine and arginine residues in HDPs. Here, we explore the impact of amine group variation (primary, secondary, or tertiary amine) on the antibacterial performance of HDP-mimicking beta-peptide polymers. Our studies show that a secondary ammonium is superior to either a primary ammonium or a tertiary ammonium as the cationic moiety in antibacterial beta-peptide polymers. The optimal polymer, a homopolymer bearing secondary amino groups, displays potent antibacterial activity and the highest selectivity (low hemolysis and cytotoxicity). The optimal polymer displays potent activity against antibiotic-resistant bacteria and high therapeutic efficacy in treating MRSA-induced wound infections and keratitis as well as low acute dermal toxicity and low corneal epithelial cytotoxicity. This work suggests that secondary amines may be broadly useful in the design of antibacterial polymers.