Abstract Lipopeptides are known to show bactericidal activity and due to their simple structure, ease of design, and low cost of implementation, they are often considered potent replacement for many traditional antibiotics. Another important advantage of lipopeptides is related to the fact that their preferential target is a cell membrane. Hence their action is less specific than conventional antibiotics, which means that development of drug resistance by pathogens is less probable in such case. In this paper we have utilized electrochemical methods and in situ atomic force microscopy to evaluate the mode of action of novel lipopeptide C15H31CO-DPhe-Dab-Dab-Leu-NH2 on planar lipid bilayer. The latter was composed of phosphatidylethanolamines and phosphatidylglycerols extracts from E. coli. Therefore it can be considered as a simplified model of inner membrane of Gram negative bacteria. We have found that lipopeptide-lipid interactions strongly affect molecular organization of PE/PG bilayer, which is reflected by increased disorder and subsequent perforation of the film. Importantly, fluid domains were identified as preferential sites for insertion of lipopeptide molecules, which tend to accumulate within the membrane. However, above certain threshold ratio the membrane becomes swollen and strongly destabilized. This results in membrane rupture and large mixed lipopeptide-lipid aggregates departure from electrode surface. Based on experimental observations, the mechanism of C16-fXXL action on bacterial-like model membrane is proposed.

中文翻译：

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脂肽诱导的由细菌膜脂组成的固体支撑双层渗透性的变化

摘要 众所周知，脂肽具有杀菌活性，由于其结构简单、易于设计和实施成本低，它们通常被认为是许多传统抗生素的有效替代品。脂肽的另一个重要优势与它们的优先靶标是细胞膜这一事实有关。因此，它们的作用不如传统抗生素特异性，这意味着在这种情况下，病原体产生耐药性的可能性较小。在本文中，我们利用电化学方法和原位原子力显微镜来评估新型脂肽 C15H31CO-DPhe-Dab-Dab-Leu-NH2 对平面脂双层的作用模式。后者由来自大肠杆菌的磷脂酰乙醇胺和磷脂酰甘油提取物组成。因此它可以被认为是革兰氏阴性菌内膜的简化模型。我们发现脂肽-脂质相互作用强烈影响 PE/PG 双层的分子组织，这反映在膜的无序增加和随后的穿孔上。重要的是，流体域被确定为脂肽分子插入的优先位点，这些分子倾向于在膜内积累。然而，高于一定的阈值比率，膜变得肿胀和强烈不稳定。这导致膜破裂和大的混合脂肽-脂质聚集体离开电极表面。基于实验观察，提出了C16-fXXL对类细菌模型膜的作用机制。我们发现脂肽-脂质相互作用强烈影响 PE/PG 双层的分子组织，这反映在膜的无序增加和随后的穿孔上。重要的是，流体域被确定为脂肽分子插入的优先位点，这些分子倾向于在膜内积累。然而，高于一定的阈值比率，膜变得肿胀和强烈不稳定。这导致膜破裂和大的混合脂肽-脂质聚集体离开电极表面。基于实验观察，提出了C16-fXXL对类细菌模型膜的作用机制。我们发现脂肽-脂质相互作用强烈影响 PE/PG 双层的分子组织，这反映在膜的无序增加和随后的穿孔上。重要的是，流体域被确定为脂肽分子插入的优先位点，这些分子倾向于在膜内积累。然而，高于一定的阈值比率，膜变得肿胀和强烈不稳定。这导致膜破裂和大的混合脂肽-脂质聚集体离开电极表面。基于实验观察，提出了C16-fXXL对类细菌模型膜的作用机制。流体结构域被确定为脂肽分子插入的优先位点，这些分子倾向于在膜内积累。然而，高于一定的阈值比率，膜变得肿胀和强烈不稳定。这导致膜破裂和大的混合脂肽-脂质聚集体离开电极表面。基于实验观察，提出了C16-fXXL对类细菌模型膜的作用机制。流体结构域被确定为脂肽分子插入的优先位点，这些分子倾向于在膜内积累。然而，高于一定的阈值比率，膜变得肿胀和强烈不稳定。这导致膜破裂和大的混合脂肽-脂质聚集体离开电极表面。基于实验观察，提出了C16-fXXL对类细菌模型膜的作用机制。