Structure–activity relationship of quaternized amphiphilic poly(DMAEMA) as broad-spectrum antimicrobial peptide mimics against multidrug-resistant pathogens

Increasingly resistant to conventional antibiotics, multidrug-resistant (MDR) microorganisms remain a significant healthcare challenge. Therefore, this study uses antimicrobial peptide (AMP)-inspired design to develop antibacterial amphiphilic polymers. Four quaternary ammonium monomers were synthesized by reacting 2-(dimethylamino)ethyl methacrylate (DMAEMA) with hexyl, octyl, dodecyl and hexadecyl bromides, followed by homopolymerization to yield poly(DMAEMA-HB), poly(DMAEMA-OB), poly(DMAEMA-DB) and poly(DMAEMA-HdB). Quaternizaion was reflected in the FTIR (2850 cm−1) and 1H NMR (δ = 3.3 ppm) and the polymerization shifted the vinyl proton signals. Poly(DMAEMA-DB)’s lowest minimum inhibitory concentration (360–2500 µg/mL) indicated an optimal amphiphilic balance for antibacterial activity provided by dodecyl chain. While SEM and potassium ion leakage (737 and 98 ppb against MRSA and Escherichia coli, respectively) showed membrane disruption, hemolysis assays reported high erythrocyte toxicity across all derivatives, expressing a hydrophobicity-driven tradeoff between antibacterial potency and hemocompatibility. These results contribute important structural insights to guide the future design of safer, membrane-active antimicrobial polymers.