Effects of Secondary Amine and Molecular Weight on the Biological Activities of Cationic Amphipathic Antimicrobial Macromolecules.

Abstract

Cationic amphipathic antimicrobial agents inspired by antimicrobial peptides (AMPs) have shown potential in combating multidrug-resistant bacteria because of minimal resistance development. Here, this study focuses on the development of novel cationic amphipathic macromolecules in the form of dendrons and polymers with different molecular weights that employ secondary amine piperidine derivative as the cationic moiety. Generally, secondary amine compounds, especially at low molecular weights, have stronger bacteriostatic, bactericidal, and inner membrane disruption abilities than those of their primary amine counterparts. Low molecular weight D2 dendrons with two cationic centers and one hydrophobic dodecyl chain produce outstanding synergistic activity with the antibiotic rifampicin against Escherichia coli, where one-eighth of the standalone dose of D2 dendrons could reduce the concentration of rifampicin required by up to 4000-fold. The low molecular weight compounds are also less toxic and therefore have higher therapeutic index values compared to compounds with larger molecular weights. This study thus reveals key information that may inform the design of future synthetic AMPs and mimics, specifically, the design of low-molecular-weight compounds with secondary amine as the cationic center to achieve high antimicrobial potency and biocompatibility.