文献类型：期刊文献

英文题名：A host defense peptide-mimicking prodrug activated by drug-resistant Gram-negative bacterial infections

作者：Xie, Jiayang[1];Zhou, Min[1];Cong, Zihao[2];Xiao, Ximian[2];Liu, Longqiang[2];Chen, Sheng[2];Jiang, Weinan[3];Wu, Yueming[2];Liu, Runhui[1,2,3]

机构：[1]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Engn Res Ctr Biomed Mat, Sch Mat Sci & Engn,Minist Educ,Shanghai Frontiers, Key Lab Specially Funct Polymer Mat & Related Tech, Shanghai 200237, Peoples R China;[3]Chinese Acad Sci, Suzhou Inst Biomed Engn & Technol, Suzhou 215163, Peoples R China

年份：2025

卷号：17

期号：801

外文期刊名：SCIENCE TRANSLATIONAL MEDICINE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001501589400006)】；

基金：This research was supported by the National Key Research and Development Program of China (2022YFC2303100) (to R.L.),the National Natural Science Foundation of China [nos.T2325010 (to R.L.), 22075078 (to R.L.), 22305082 (to M.Z.), and 52203162 (to Y. W.)], the Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (Shanghai Municipal Education Commission), the Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences) (to R.L.), the Open Project of Engineering Research Center of Dairy Quality and Safety Control Technology (Ministry of Education, R202201) (to R.L.), and the Fundamental Research Funds for the Central Universities (nos. JKVD1241029 and JKD01241701).

语种：英文

摘要：The high mortality of drug-resistant Gram-negative bacterial infections and the scarcity of antibiotics against Gram-negative bacteria urgently call for effective antimicrobial agents. Antimicrobial polymers that mimic host defense peptides (HDPs) have been extensively studied, but in the complex in vivo environment, cationic polymers can interact with polyanionic macromolecules and host cells bearing polyanionic membranes, leading to undesired side effects. Here, we report an "acid-responsive antimicrobial polymer prodrug" strategy and performed a proof-of-concept treatment using HDP-mimicking poly(2-oxazoline)s. By protecting the side-chain amines with 2,3-dimethylmaleic anhydride to neutralize the positive charges, the poly(2-oxazoline) prodrug can remain stealthy under physiological conditions but expose these charges to become activated at infection sites. The poly(2-oxazoline) prodrug exhibited high biocompatibility, prolonged blood circulation time, and potent activity against drug-resistant Gram-negative bacteria and biofilms in vitro and did not develop antibacterial resistance. Moreover, the poly(2-oxazoline) prodrug showed strong therapeutic potential for both local and systemic infections. The prodrug displayed potent activity in treating Gram-negative bacteria-associated infections in multiple mouse models, including subcutaneous abscess, neutropenic thigh infection, kidney infection, lung infection, and peritonitis. These results demonstrate the effectiveness of our prodrug strategy to develop potent antibacterial agents.