The New Delhi Metallo-β-lactamase-1 Covalent Inhibitors Derived from Cephalexin Effectively Reverse Meropenem Resistance

  • J Med Chem. 2026 May 28;69(10):12398-12416. doi: 10.1021/acs.jmedchem.6c00314.
Wandong Liu  1 ,  Chenyu Liu  2 ,  Yan Guo  3 ,  Zhiying Liu  3 ,  Chen Zhang  1 ,  Wanli Meng  1 ,  Shengbiao Wan  1 ,  Sheng Chen  2 ,  Jiazhang Qiu  3 ,  Rilei Yu  1
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 Lab of Chemical Biology and Drug Discovery and the Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon 100872, Hong Kong, China.
  • 3. 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.
PMID: 42138890 DOI: 10.1021/acs.jmedchem.6c00314
Abstract

New Delhi metallo-β-lactamase-1 (NDM-1) hydrolyzes carbapenems and most β-lactam Antibiotics, posing a significant threat to global health and underscoring the urgent need for effective inhibitors. To address this unmet need, we designed a series of covalent NDM-1 inhibitors by introducing a selenazolone warhead into the cephalexin scaffold. Among them, compound 16a demonstrated the most potent inhibitory activity, with an IC50 value of 3.27 μM. The combination of 16a and meropenem (Mem) synergistically lowered the MIC of Mem 8-16-fold in NDM-1-positive isolates and potently suppressed NDM-1-positive Bacterial growth in a mouse Infection model. Mechanistically, 16a forms a stable Se-S bond with Cys208 at the NDM-1 active site through its selenazolone warhead, enabling prolonged target engagement and sustained enzyme inhibition. Collectively, these findings demonstrate that covalent inhibitors derived from the cephalexin scaffold represent a promising strategy for combating NDM-1-mediated resistance, offering valuable leads for targeting metallo-β-lactamases.

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