Cationic Polymers Based on a Polyester Backbone Possessing Potent Antimicrobial Activity against Drug-Resistant Bacteria

Multidrug resistance (MDR) infections pose a critical challenge to antibacterial therapy by reducing the efficacy of antibiotics. However, achieving potent antimicrobial activity and excellent biocompatibility while employing simplified and generalized structures remains an open challenge. Herein, we report a new class of cationic and amphiphilic Poly(<i>ε</i>-caprolactone) (PCL) derivatives, rationally designed as synthetic mimics of host defense peptides (HDPs), based on structurally simplified polyester backbone. The polyester backbone inherently fulfills the role of hydrophobic amino acids in HDPs, enabling the design of antibacterial polymers with superior bactericidal performance and biocompatibility without the need for additional hydrophobic side chains. The optimal polymer, PKCL₄₅, exhibits broad-spectrum antibacterial activities even at 1 μg/mL, potent activity to eradicate mature biofilms and is insusceptible to MDR, and mice <i>in vivo</i> studies confirm its systemic safety. Collectively, the polyester-backbone antimicrobial polymers demonstrate a promising candidate for antibacterial treatment, which provides a strategy for clinical antimicrobial agent design.