Non-amphiphilic polycations have recently been recognized to hold excellent antimicrobial potential with great mammalian cell compatibility. In a recent study, the excellent broad-spectrum bactericidal efficacy of a quaternary ammonium-substituted cationic pullulan (CP4) was demonstrated. Their selective toxicity and nominal probability to induce the acquisition of resistance among pathogens fulfill the fundamental requirements of new-generation antibacterials. However, there have been exiguous attempts in the literature to understand the antimicrobial activity of polycations against Gram-positive bacterial membranes. Here, for the first time, we have scrutinized the molecular level interactions of CP4 tetramers with a model Staphylococcus aureus membrane to understand their probable antibacterial function using molecular dynamics simulations. Our analysis reveals that the hydrophilic CP4 molecules are spontaneously adsorbed onto the membrane outer leaflet surface by virtue of strong electrostatic interactions and do not penetrate into the lipid tail hydrophobic region. This surface binding of CP4 is strengthened by the formation of anionic lipid-rich domains in their vicinity, causing lateral compositional heterogeneity. The major outcomes of the asymmetric accumulation of bulky polycationic CP4 on one leaflet are (i) anionic lipid segregation at the interaction site and (ii) a decrease in the cationic lipid acyl tail ordering and ease of water translocation across the lipid hydrophobic barrier. The membrane–CP4 interactions are strongly monitored by the ionic strength; a higher salt concentration weakens the binding of CP4 on the membrane surface. In addition, our study also substantiates the non-interacting behavior of CP4 oligomers with biomimetic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane, indicating their cell selectivity and specificity against pathogenic membranes.

中文翻译：

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阴离子脂质簇介导的季铵盐取代聚阳离子普鲁兰多糖对金黄色葡萄球菌细菌膜的杀菌活性和选择性毒性

非两亲性聚阳离子最近被认为具有出色的抗菌潜力和良好的哺乳动物细胞相容性。在最近的一项研究中，证明了季铵取代的阳离子支链淀粉 (CP4) 具有出色的广谱杀菌功效。它们的选择性毒性和诱导病原体获得耐药性的名义概率满足了新一代抗菌剂的基本要求。然而，在文献中已经很少尝试了解聚阳离子对革兰氏阳性细菌膜的抗菌活性。在这里，我们第一次仔细研究了 CP4 四聚体与金黄色葡萄球菌模型的分子水平相互作用使用分子动力学模拟来了解其可能的抗菌功能。我们的分析表明，亲水性 CP4 分子通过强静电相互作用自发吸附到膜外小叶表面上，并且不会渗透到脂质尾部疏水区域。CP4 的这种表面结合通过在其附近形成富含阴离子的富含脂质的结构域而得到加强，从而导致横向成分异质性。大体积聚阳离子 CP4 在一个小叶上不对称积累的主要结果是 (i) 相互作用位点的阴离子脂质分离和 (ii) 阳离子脂质酰基尾序的减少和跨脂质疏水屏障的水易位。离子强度强烈监测膜-CP4 相互作用；较高的盐浓度会削弱 CP4 在膜表面的结合。此外，我们的研究还证实了 CP4 低聚物与仿生 1-palmitoyl-2-oleoyl- 的非相互作用行为。sn -glycero-3-phosphocholine (POPC) 膜，表明它们对病原膜的细胞选择性和特异性。