Lu Yiwen, Geng Wen, Li Lili, Xie Fang, Zhang Mingchang, Xie Huatao, Cai Jie
Institute of Hepatobiliary Diseases, Transplant Center, Zhongnan Hospital, Hubei Engineering Center of Natural Polymers-based Medical Materials, Key Laboratory of Biomedical Polymers of Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China.
Department of Ophthalmology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Int J Biol Macromol. 2025 Apr;298:140052. doi: 10.1016/j.ijbiomac.2025.140052. Epub 2025 Jan 18.
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.
多重耐药（MDR）细菌感染对全球公共卫生构成严重威胁，给细菌性角膜炎的治疗带来重大挑战。抗菌药物耐药性（AMR）的升级凸显了对替代治疗策略的迫切需求。在本研究中，我们报告了使用酸碱顺序组合方法均匀合成季铵化超高度脱乙酰壳聚糖（QUDCS）。优化后的QUDCS-2通过由静电、氢键和疏水相互作用驱动的膜破坏机制表现出广谱抗菌活性，同时保持低细胞毒性和高选择性。与脱乙酰程度较低的同类物相比，QUDCS-2在富含酶的环境中表现出卓越的稳定性，并有效抑制和根除耐甲氧西林金黄色葡萄球菌（MRSA）和铜绿假单胞菌的成熟生物膜。此外，QUDCS-2表现出显著的防止抗菌药物耐药性产生的能力。在小鼠角膜炎模型中，QUDCS-2显示出优异的生物相容性和显著的抗菌效果，为其作为长期有效抗菌剂的潜力提供了有力支持。
