Optimal Balance of Hydrophobic Content and Degree of Polymerization Results in a Potent Membrane-Targeting Antibacterial Polymer

[Image: see text] Globally, excessive use of antibiotics has drastically raised the resistance frequency of disease-causing microorganisms among humans, leading to a scarcity of efficient and biocompatible drugs. Antimicrobial polymers have emerged as a promising candidate to combat drug-resistance pathogens. Along with the amphiphilic balance, structural conformation and molecular weight (M(n)) play an indispensable role in the antimicrobial potency and cytotoxic activity of polymers. Here, we synthesize cationic and amphiphilic methacrylamide random copolymers using free-radical copolymerization. The mole fraction of the hydrophobic groups is kept constant at approximately 20%, while the molecular weight (average number of linked polymeric units) is varied and the antibacterial and cytotoxic activities are studied. The chemical composition of the copolymers is characterized by (1)H NMR spectroscopy. We observe that the average number of linked units in a polymer chain (i.e., molecular weight) significantly affects the polymer activity and selectivity. The antibacterial efficacy against both of the examined bacteria, Escherichia coli and Staphylococcus aureus, increases with increasing molecular weight. The bactericidal activity of polymers is confirmed by live/dead cell viability assay. Polymers with high molecular weight display high antibacterial activity, yet are highly cytotoxic even at 1 × MIC. However, low-molecular-weight polymers are biocompatible while retaining antibacterial potency. Furthermore, no resistance acquisition is observed against the polymers in E. coli and S. aureus. A comprehensive analysis using confocal and scanning electron microscopy (SEM) techniques shows that the polymers target bacterial membranes, resulting in membrane permeabilization that leads to cell death.