High Antibacterial Activity and Selectivity of Cationic Disubstituted Polypeptoids with Stable Helices and Enzymatic Resistance

High antibacterial activity, low mammalian cell toxicity, and serum stability are crucial parameters for designing efficient antibacterial materials under physiological conditions. This relies on a deep understanding of the structure–property relationship of antibacterial materials. In this study, a series of cationic amphiphilic disubstituted polypeptoids were synthesized by using ring-opening polymerization (ROP) followed by thiol-ene click reactions. This new class of peptidomimetic materials, with chiral centers at backbones and ammonium alkyl N -substituents, exhibited remarkably stable helical structures independent of pH, temperature, salt, and denaturing agents. The helical analogs were found to show higher antibacterial activity against both Gram-negative and Gram-positive strains than the racemic, nonhelical counterparts. The helical structure and the balance of cationic charges and hydrophobicity were key parameters to achieve high selectivity for bacteria over mammalian cells. Moreover, unlike poly( l -lysine), the disubstituted polypeptoids, with stable helices and enzymatic resistance, retained high antibacterial activity even in the presence of salts, human serum albumin (HSA), and protease trypsin at physiological concentrations. This study deepens our understanding of how structural elements correlate with antibacterial activity and selectivity. In addition, the helical and enzymatically stable disubstituted polypeptoids have shown promise as an attractive platform for the design of new antibacterial materials with high efficiency and low toxicity.