Liu Wandong, Guo Yan, Zhang Chen, Liu Chenyu, Chen Sheng, Li Xiaoyang, Qiu Jiazhang, Wan Shengbiao
Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266071, China.
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, 130062, China.
Eur J Med Chem. 2025 Mar 5;285:117243. doi: 10.1016/j.ejmech.2025.117243. Epub 2025 Jan 6.
The emergence of New Delhi metallo-β-lactamase-1 (NDM-1) poses a significant threat to the clinical application of antibiotics, as it possesses the ability to hydrolyze nearly all β-lactam antibiotics. Regrettably, there are currently no clinical drugs targeting NDM-1, making it imperative to develop highly potent and minimally toxic NDM-1 inhibitors. Herein, a series of molecular Trojan horses targeting NDM-1 were synthesized by introducing ebselen into 7-aminocephalosporanic acid derivatives via a C-Se bond. Representative compound 18b exhibited potent inhibitory activity against NDM-1, with an IC value of 7.03 μM, and combining with meropenem (Mem) decreased the minimum inhibitory concentration (MIC) of Mem by 4-32-fold in NDM-1 expressing bacteria. Mechanistically, 18b released the ebselen moiety at the active site of NDM-1, forming a Se-S bond with Cys208 to achieve targeted drug delivery of ebselen. Importantly, 18b demonstrated potent inhibition of resistant bacterial growth and replication in mice when administered in combination with Mem. These results suggest that 18b is a promising candidate for treating infections caused by resistant bacteria expressing NDM-1.
新德里金属β-内酰胺酶-1（NDM-1）的出现对抗生素的临床应用构成了重大威胁，因为它能够水解几乎所有的β-内酰胺抗生素。遗憾的是，目前尚无针对NDM-1的临床药物，因此开发高效且低毒的NDM-1抑制剂势在必行。在此，通过经由C-Se键将依布硒啉引入7-氨基头孢烷酸衍生物中，合成了一系列靶向NDM-1的分子特洛伊木马。代表性化合物18b对NDM-1表现出强效抑制活性，IC值为7.03 μM，并且与美罗培南（Mem）联合使用可使表达NDM-1的细菌中Mem的最低抑菌浓度（MIC）降低4至32倍。从机制上讲，18b在NDM-1的活性位点释放出依布硒啉部分，与Cys208形成Se-S键以实现依布硒啉的靶向药物递送。重要的是，18b与Mem联合给药时在小鼠中表现出对耐药细菌生长和复制的强效抑制作用。这些结果表明，18b是治疗由表达NDM-1的耐药细菌引起的感染的有前景的候选药物。
