Hu Xiaowen, Li Dongdong, Li Huaping, Piao Yinzi, Wan Hongping, Zhou Tieli, Karimi Mahdi, Zhao Xinghong, Li Yuanfeng, Shi Linqi, Liu Yong
Joint Centre of Translational Medicine, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Department of Orthodontics School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, 325027, China.
Adv Mater. 2024 Sep;36(36):e2406156. doi: 10.1002/adma.202406156. Epub 2024 Jul 18.
Polymyxins have been regarded as an efficient therapeutic against many life-threatening, multidrug resistant Gram-negative bacterial infections; however, the cytotoxicity and emergence of drug resistance associated with polymyxins have greatly hindered their clinical potential. Herein, the reaction-induced self-assembly (RISA) of polymyxins and natural aldehydes in aqueous solution is presented. The resulting assemblies effectively mask the positively charged nature of polymyxins, reducing their cytotoxicity. Moreover, the representative PMBA (composed of polymyxin B (PMB) and (E)-2-heptenal (A)) assemblies demonstrate enhanced binding to Gram-negative bacterial outer membranes and exhibit multiple antimicrobial mechanisms, including increased membrane permeability, elevated bacterial metabolism, suppression of quorum sensing, reduced ATP synthesis, and potential reduction of bacterial drug resistance. Remarkably, PMBA assemblies reverse drug resistance in clinically isolated drug-resistant strains of Gram-negative bacteria, demonstrating exceptional efficacy in preventing and eradicating bacterial biofilms. PMBA assemblies efficiently eradicate Gram-negative bacterial biofilm infections in vivo and alleviate inflammatory response. This RISA strategy offers a practical and clinically applicable approach to minimize side effects, reverse drug resistance, and prevent the emergence of resistance associated with free polymyxins.
多粘菌素被认为是治疗许多危及生命的多重耐药革兰氏阴性菌感染的有效药物；然而，与多粘菌素相关的细胞毒性和耐药性的出现极大地阻碍了它们的临床应用潜力。在此，本文介绍了多粘菌素与天然醛在水溶液中的反应诱导自组装（RISA）。所形成的组装体有效地掩盖了多粘菌素的正电荷性质，降低了它们的细胞毒性。此外，具有代表性的PMBA（由多粘菌素B（PMB）和（E）-2-庚烯醛（A）组成）组装体显示出与革兰氏阴性菌外膜的结合增强，并表现出多种抗菌机制，包括增加膜通透性、提高细菌代谢、抑制群体感应、减少ATP合成以及可能降低细菌耐药性。值得注意的是，PMBA组装体可逆转临床分离的革兰氏阴性菌耐药菌株的耐药性，在预防和根除细菌生物膜方面显示出卓越的疗效。PMBA组装体在体内有效地根除革兰氏阴性菌生物膜感染并减轻炎症反应。这种RISA策略提供了一种实用且临床适用的方法，可将副作用降至最低、逆转耐药性并防止与游离多粘菌素相关的耐药性出现。
