Peptides exert important biological functions but their application is hindered by their susceptibility to proteolysis and poor stability in vivo. Thus, functional peptide mimics have drawn a great deal of attention to address this challenge. Poly(2-oxazoline)s, a class of biocompatible and proteolysis-resistant polymer, can work as host defense peptide mimics without following the general membrane-targeting mechanism as shown in our previous work. This observation encouraged us to figure out if poly(2-oxazoline)s are special and break the general membrane-targeting mechanism of host defense peptides and their mimics. In this study, we aimed at the connection between structure and antibacterial mechanism of poly(2-oxazoline)s. A new γ-aminobutyric acid (GABA)-pendent poly(2-oxazoline) was synthesized and investigated to compare with glycine-pendent poly(2-oxazoline) in our previous study, with the former polymer has two extra CH₂ groups in the sidechain to increase the hydrophobicity and amphiphilicity. Membrane depolarization assay suggested that incorporating two more CH₂ groups into the sidechain of poly(2-oxazoline) resulted in a mechanism switch from DNA-targeting to membrane-targeting, which was supported by the slow time-kill kinetics and slightly distorted and sunken membrane morphology. Besides, GABA-pendent poly(2-oxazoline) showed potent activity against methicillin-resistant S. aureus and low hemolysis on human red blood cells. Moreover, repeated use of the antimicrobial poly(2-oxazoline) did not stimulate bacteria to obtain resistance, which was an obvious advantage of membrane-targeting antimicrobial agents.

肽发挥重要的生物学功能，但由于其对蛋白水解的敏感性和体内的不良稳定性而受到阻碍。因此，功能性肽模拟物引起了极大的关注以应对这一挑战。聚（2-恶唑啉）是一类具有生物相容性和耐蛋白水解性的聚合物，可以用作宿主防御肽模拟物，而无需遵循我们先前工作中所示的一般膜靶向机制。该观察结果鼓励我们弄清楚聚（2-恶唑啉）是否特殊，并打破了宿主防御肽及其模拟物的一般膜靶向机制。在这项研究中，我们针对聚（2-恶唑啉）s的结构与抗菌机制之间的联系。在我们以前的研究中，合成了一种新的γ-氨基丁酸（GABA）-悬垂型聚（2-恶唑啉），并将其与甘氨酸-悬垂的聚（2-恶唑啉）进行了比较，前一种聚合物具有两个额外的CH ₂侧链中的基团增加疏水性和两亲性。膜去极化测定表明，在聚（2-恶唑啉）的侧链中再引入两个CH ₂基团会导致从DNA靶向转变为膜靶向的机制，这是由缓慢的时间杀灭动力学和轻微扭曲和下陷所支持的膜形态。此外，GABA悬垂型聚（2-恶唑啉）对耐甲氧西林的金黄色葡萄球菌显示出有效的活性，并且对人的红细胞的溶血性低。此外，重复使用抗微生物剂聚（2-恶唑啉）不会刺激细菌获得耐药性，这是靶向膜的抗微生物剂的明显优势。