Mechanistic Study on the Antibacterial Activity of Self-Assembled Poly(aryl ether)-Based Amphiphilic Dendrimers.

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 (, , , and ) containing terminal amine (PAMAM-based), ester, and hydrazide functional groups with varied hydrophobicity. Among the four dendrimers under study, the amine-terminated dendrimer () displayed potent antibacterial activity. The ratio of surface cationic charge to hydrophobicity had a significant effect on the antibacterial activity, where dendrimer with increased surface cationic charges exhibited a higher minimum inhibitory concentration (MIC) than . (ester terminated) and (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 in comparison with . Molecular dynamics simulations of and on bacterial membrane patches further corroborated the experimental findings. The structural conformation of dendrimer facilitated increased membrane interaction compared to dendrimer. 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 () 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.