细菌对常规抗生素的耐药性的增加的威胁已经保证需要开发膜靶向抗菌剂。近年来，已经报道了几种具有不同超分子结构的自组装阳离子两亲物具有增强的特异性的有效抗菌活性。在这项研究中,我们描述了含有末端胺（基于PAMAM）的四种低代聚（芳基醚）基两亲性树枝状聚合物（AD-1，AD-2，AD-3和AD-4）的自组装和抗菌活性，酯,和具有不同疏水性的酰肼官能团。在研究的四种树枝状聚合物中，胺封端的树枝状聚合物（AD-1）显示出有效的抗菌活性。表面阳离子电荷与疏水性之比对抗菌活性有显著影响,其中具有增加的表面阳离子电荷的AD-3树枝状聚合物表现出比AD-1更高的最小抑制浓度(MIC)。AD-2(酯封端的)和AD-4(酰肼封端的)树枝状聚合物不显示任何杀菌活性。两亲性树枝状聚合物-细菌相互作用，通过结合研究进一步验证，还显示了细菌形态的显着变化，有效的膜渗透，与AD-3相比，AD-1的去极化。细菌膜斑块上AD-1和AD-3的分子动力学模拟进一步证实了实验发现。与AD-3树枝状聚合物相比,AD-1树枝状聚合物的结构构象促进增加的膜相互作用。AD-1还显示了对细菌膜的选择性，超过成纤维细胞（4×MIC），证实了最佳疏水性对于无细胞毒性的有效抗菌活性的重要性。自组装（基于聚（芳基醚）-PAMAM的）树枝状聚合物（AD-1）与常规的高代树枝状聚合物相比也表现出有效的抗菌活性，建立杀菌活性的自组装的含义。此外，详细的机理研究表明，两亲性树枝状聚合物疏水性的优化调整在细菌的膜破坏中起着至关重要的作用。我们相信，这项研究将为两亲性树枝状聚合物作为有效破坏膜的抗菌剂的设计策略提供有价值的见解。
The increased threat of bacterial resistance against conventional antibiotics has warranted the need for development of membrane targeting antibacterial agents. Several self-assembled cationic amphiphiles with different supramolecular structures have been reported in recent years for potent antibacterial activity with increased specificity. In this
study, we describe the self-assembly and antibacterial activity of four lower generation poly(aryl ether)-based amphiphilic dendrimers (AD-1, AD-2, AD-3, and AD-4) containing terminal amine (PAMAM-based), ester, and hydrazide functional groups with varied hydrophobicity. Among the four dendrimers under
study, the amine-terminated dendrimer (AD-1) displayed potent antibacterial activity. The ratio of surface cationic charge to hydrophobicity had a significant effect on the antibacterial activity, where AD-3 dendrimer with increased surface cationic charges exhibited a higher minimum inhibitory concentration (MIC) than AD-1. AD-2 (ester terminated) and AD-4 (hydrazide terminated) dendrimers did not show any bactericidal activity. The amphiphilic dendrimer-bacteria interactions, further validated by binding studies, also showed significant changes in bacterial morphology, effective membrane permeation, and depolarization by AD-1 in comparison with AD-3. Molecular dynamics simulations of AD-1 and AD-3 on bacterial membrane patches further corroborated the experimental findings. The structural conformation of AD-1 dendrimer facilitated increased membrane interaction compared to AD-3 dendrimer. AD-1 also displayed selectivity to bacterial membranes over fibroblast cells (4× MIC), corroborating the significance of an optimal hydrophobicity for potent antibacterial activity with no cytotoxicity. The self-assembled (poly(aryl ether)-PAMAM-based) dendrimer (AD-1) also exhibited potent antibacterial activity in comparison with conventional higher generation dendrimers, establishing the implication of self-assembly for bactericidal activity. Moreover, the detailed mechanistic
study reveals that optimal tuning of the hydrophobicity of amphiphilic dendrimers plays a crucial role in membrane disruption of bacteria. We believe that this
study will provide valuable insights into the design strategies of amphiphilic dendrimers as antibacterial agents for efficient membrane disruption.
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