Enhanced antibacterial and antibiofilm activities of quaternized ultra-high deacetylated chitosan against multidrug-resistant bacteria

Multidrug-resistant (MDR) bacterial infections pose a severe threat to global public health and present significant challenges in the treatment of bacterial keratitis. The escalation of antimicrobial resistance (AMR) underscores the urgent need for alternative therapeutic strategies. In this study, we report the homogeneous synthesis of quaternized ultra-highly deacetylated chitosan (QUDCS) using a sequential acid-base combination approach. The optimized QUDCS-2 exhibits broad-spectrum antibacterial activity through a membrane-disruption mechanism driven by electrostatic, hydrogen bonding, and hydrophobic interactions, while maintaining low cytotoxicity and high selectivity. Compared to less deacetylated counterparts, QUDCS-2 demonstrates superior stability in enzyme-rich environments and effectively inhibits and eradicates mature biofilms of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Furthermore, QUDCS-2 exhibits a remarkable ability to prevent the development of antimicrobial resistance. In a mouse keratitis model, QUDCS-2 shows excellent biocompatibility and significant antibacterial efficacy, providing strong support for its potential as a long-term, effective antimicrobial agent.