Xie Jiayang, Zhou Min, Cong Zihao, Xiao Ximian, Liu Longqiang, Chen Sheng, Jiang Weinan, Wu Yueming, Liu Runhui
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Engineering Research Center for Biomedical Materials of Ministry of Education, Key Laboratory of Specially Functional Polymeric Materials and Related Technology (Ministry of Education), School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.
Sci Transl Med. 2025 Jun 4;17(801):eadl4870. doi: 10.1126/scitranslmed.adl4870.
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.
耐药革兰氏阴性菌感染的高死亡率以及针对革兰氏阴性菌的抗生素稀缺，迫切需要有效的抗菌剂。模拟宿主防御肽（HDPs）的抗菌聚合物已得到广泛研究，但在复杂的体内环境中，阳离子聚合物可与多阴离子大分子以及带有多阴离子膜的宿主细胞相互作用，导致不良副作用。在此，我们报告一种“酸响应抗菌聚合物前药”策略，并使用模拟HDP的聚（2-恶唑啉）进行了概念验证治疗。通过用2,3-二甲基马来酸酐保护侧链胺以中和正电荷，聚（2-恶唑啉）前药在生理条件下可保持隐身状态，但在感染部位暴露这些电荷从而被激活。聚（2-恶唑啉）前药表现出高生物相容性、延长的血液循环时间以及在体外对耐药革兰氏阴性菌和生物膜的强效活性，并且不会产生抗菌耐药性。此外，聚（2-恶唑啉）前药对局部和全身感染均显示出强大的治疗潜力。该前药在多种小鼠模型中治疗革兰氏阴性菌相关感染时表现出强效活性，包括皮下脓肿、中性粒细胞减少性大腿感染、肾脏感染、肺部感染和腹膜炎。这些结果证明了我们的前药策略在开发强效抗菌剂方面的有效性。
