2. Academic Validation
  3. Development of molecular Trojan horses targeting New Delhi metallo-β-lactamase-1 for the restoration of meropenem susceptibility in drug-resistant bacteria

Development of molecular Trojan horses targeting New Delhi metallo-β-lactamase-1 for the restoration of meropenem susceptibility in drug-resistant bacteria

  • Eur J Med Chem. 2025 Mar 5:285:117243. doi: 10.1016/j.ejmech.2025.117243.
Wandong Liu 1,  Yan Guo 2,  Chen Zhang 1,  Chenyu Liu 3,  Sheng Chen 3,  Xiaoyang Li 4,  Jiazhang Qiu 5,  Shengbiao Wan 6
Affiliations

Affiliations

  • 1 Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266071, China.
  • 2 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.
  • 3 State Key Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, 100872, China.
  • 4 Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266071, China. Electronic address: lixiaoyang@ouc.edu.cn.
  • 5 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. Electronic address: qiujz@jlu.edu.cn.
  • 6 Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266071, China. Electronic address: biaowan@ouc.edu.cn.
PMID: 39798399 DOI: 10.1016/j.ejmech.2025.117243
Abstract

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 IC50 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.

Keywords

Ebselen; Molecular Trojan horses; New Delhi metallo-β-lactamase-1; Target inhibitor.

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