An Antimicrobial Peptide-Mimetic Methacrylate Random Copolymer Induces Domain Formation in a Model Bacterial Membrane
An Antimicrobial Peptide-Mimetic Methacrylate Random Copolymer Induces Domain Formation in a Model Bacterial Membrane
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DOI：
10.1007/s00232-022-00220-6
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发表时间：
2022-02
期刊：
影响因子：
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通讯作者：
K. Yasuhara;Manami Tsukamoto;J. Kikuchi;K. Kuroda
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文献类型：
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作者：
K. Yasuhara;Manami Tsukamoto;J. Kikuchi;K. Kuroda
为了解决新出现的耐药细菌问题，已经设计和开发了膜活性合成聚合物来模拟宿主防御抗菌肽（AMP）作为抗生素替代品。在这项研究中，我们研究了域的形成诱导合成聚合物模拟AMP使用模型膜，以阐明生物物理学原理，管理其膜活性机制。为此，脂质囊泡模仿大肠杆菌（E。使用1-棕榈酰基-2-油酰基-sn-甘油基-3-磷酸乙醇胺（POPE）和1-棕榈酰基-2-油酰基-sn-甘油基-3-磷酸-（1′-rac-甘油）钠盐（POPG）的8：2（摩尔比）混合物制备膜。我们的研究使用差示扫描量热法（DSC）和荧光显微镜表明，阳离子两亲性甲基丙烯酸酯无规共聚物诱导相分离，形成POPE或POPG丰富的域。罗丹明标记的聚合物也显示出与膜中分离的结构域的结合。基于这些结果，我们提出的机制，共聚物诱导域的形成类似于天然AMP的阴离子POPG脂质的聚类。此外，聚合物与GUV膜结合的时间过程呈S形，表明膜结合中存在正反馈回路。我们还假设聚合物的这种合作结合是由结构域形成驱动的。这项研究证明了两亲性共聚物调节细胞膜脂质组织的潜力，这可能为设计膜活性抗菌剂提供新的策略。图形摘要
To address the emerging issue of drug-resistant bacteria, membrane-active synthetic polymers have been designed and developed to mimic host-defense antimicrobial peptides (AMPs) as antibiotic alternatives. In this study, we investigated the domain formation induced by synthetic polymer mimics of AMPs using model membranes to elucidate the biophysical principles that govern their membrane-active mechanisms. To that end, lipid vesicles mimickingEscherichia coli(E. coli) membrane were prepared using an 8:2 (molar ratio) mixture of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), sodium salt (POPG). Our studies using differential scanning calorimetry (DSC) and fluorescence microscopy indicated that cationic amphiphilic methacrylate random copolymers induced the phase separation to form POPE- or POPG-rich domains. A rhodamine-labeled polymer also showed the binding to separated domains in the membrane. Based on these results, we propose the mechanism that the copolymers induce domain formation by clustering of anionic POPG lipids similar to natural AMPs. In addition, the time-course of polymer binding to the GUV membrane was sigmoidal, suggesting the positive feedback loop in the membrane binding. We also hypothesize that this cooperative binding of the polymer is driven by the domain formation. This study demonstrates the potential of the amphiphilic copolymers to modulate the lipid organization of cell membranes, which may provide a new strategy to design membrane-active antimicrobial agents.Graphical Abstract