Methacrylamide based antibiotic polymers with no detectable bacterial resistance

The growing number of multidrug-resistant pathogens is a major healthcare concern. In search of alternatives to antibiotics, synthetic mimics of antimicrobial peptides (SMAMPs) in the form of antimicrobial polymers have gained tremendous attention. Here, we report the synthesis of a set of 7 amphiphilic water-soluble cationic copolymers using aminopropyl methacrylamide and benzyl methacrylamide repeat units that show significant antibacterial activity. The antibacterial activity was evaluated using a broth microdilution assay against S. aureus and E. coli, while toxicity to mammalian cells was quantified by hemolysis assay with human red blood cells (RBCs). We find that the antibacterial activity and selectivity of the polymers depends on the mole fraction of aromatic benzyl units (fbenzyl) and the average molecular weight (Mn). Polymers with fbenzyl of 0.10 and 0.19, named AB-10 and AB-19 respectively, exhibited the highest antibacterial efficacy without inducing hemolysis and were chosen for further study. Liposome dye leakage study and observations from confocal and scanning electron microscopy indicate that the AB polymers killed bacterial cells primarily by disrupting the cytoplasmic membrane. No resistant mutants of E. coli and S. aureus were obtained with AB-19 in a 30 day serial passage study.