Cyclic Poly(α-amino acid) Quaternary Ammonium Salt with Potent Antibacterial Activity and Low Toxicity

Cationic antibacterial polymers have been extensively investigated as alternatives to antibiotics to address the challenges of antibiotic-resistant bacteria. However, their inevitable cytotoxicity significantly restricts their practical application. Cyclization strategies provide a reference for solving this dilemma. In this study, we designed and synthesized a series of cyclic cationic poly(α-amino acid) quaternary ammonium salts with potent antibacterial activity and low toxicity. Notably, the optimal polymer, <i>c</i>PCHLG₁₀-C₈, demonstrated remarkable antibacterial activity coupled with low cytotoxicity, exhibiting a selectivity index (SI = 128) against <i>S. aureus</i> that was 8-fold higher than the corresponding linear structure <i>l</i>PCHLG₁₀-C₈ (SI = 16). Circular dichroism spectroscopy results indicated that the cyclic structure contributed to reduced cytotoxicity by diminishing the degree of α-helix conformation. Additionally, <i>c</i>PCHLG₁₀-C₈ displayed rapid bactericidal properties, negligible propensity to induce bacterial resistance, and effectively inhibited or cleared bacterial biofilms. Furthermore, in a mouse epidermal wound infection model, <i>c</i>PCHLG₁₀-C₈ showed outstanding in vivo antibacterial effects. Hence, this study offers a promising approach for designing cationic polymers that balance antimicrobial activity and biocompatibility.