Polyaspartamide-based antimicrobials for combatting bacterial infections

The increasing challenge of antimicrobial resistance has stimulated research on antibacterial polymers, which offer enhanced therapeutic potential due to their facile synthesis, low immunogenicity, and superior stability compared to natural antimicrobial peptides. Herein, a series of cationic polyaspartamides (PASP_nDA_m) with different side chain lengths (m) and degrees of polymerization (n) were synthesized through ammonolysis reaction of poly(β-benzyl-L-aspartate) (PBLA) to systematically investigate their antibacterial activity and biocompatibility. All PASP_nDA_m exhibited antibacterial activity. Among the PASP_nDA_m, PASP₁₀DA₆ (degree of polymerization of 10, bearing side chains modified with 1,6-hexamethylenediamine) displayed potent activities against bacteria (S. aureus and E. coli, MIC = 7.8 μg mL^-1) and had the highest selectivity index of 96. Further mechanistic study revealed that PASP₁₀DA₆ killed bacteria by disrupting the integrity of the bacterial membrane, thereby leading to bacterial death. Based on this unique bactericidal mechanism, PASP₁₀DA₆ showed fast bacterial killing kinetics and was less likely to induce bacterial resistance for up to 15 generations. In a mouse skin bacterial infection model, PASP₁₀DA₆ showed effective in vivo antibacterial activity and negligible toxicity. Hence, this study provides a promising strategy for treating clinical bacterial infections.