2. Academic Validation
  3. A synergistic-available and high-potent New Delhi metallo-β-lactamase-1 (NDM-1) covalent inhibitor by the modification of naturally occurring 3-formyl chromone

A synergistic-available and high-potent New Delhi metallo-β-lactamase-1 (NDM-1) covalent inhibitor by the modification of naturally occurring 3-formyl chromone

  • Bioorg Chem. 2025 Sep:164:108902. doi: 10.1016/j.bioorg.2025.108902.
Yaowen Liang 1,  Manna Huang 2,  Xinhai Zhu 3,  Lifang Wang 1,  Yiqian Wan 1
Affiliations

Affiliations

  • 1 School of Chemical Engineering and Technology,Guangdong Engineering Technology Research Center for Platform Chemicals from Marine Biomass and Their Functionalization, Sun Yat-sen University, Zhuhai 519082, PR China.
  • 2 School of Chemical Engineering and Technology,Guangdong Engineering Technology Research Center for Platform Chemicals from Marine Biomass and Their Functionalization, Sun Yat-sen University, Zhuhai 519082, PR China. Electronic address: huangmn25@mail.sysu.edu.cn.
  • 3 Instrument Analysis & Research Center, Sun Yat-sen University, Guangzhou 510275, PR China.
PMID: 40886480 DOI: 10.1016/j.bioorg.2025.108902
Abstract

The discovery of novel NDM-1 inhibitors is one of the currently rocky and urgent tasks to fight superbug crisis. Here, we designed and synthesized three types derivatives of the 3-formyl chromone that is a naturally occurring covalent NDM-1 inhibitor. Further, their sodium bisulfite adducts have been obtained and the inhibitory activities have been explored. As a result, CS-23 has been identified to be an effective NDM-1 inhibitor with IC50 of 36 ± 4 nM. The inhibitory reversibility assay, high-resolution mass spectrometry analysis, and kinetic experiment illustrated that CS-23 was an irreversible and covalent NDM-1 inhibitor. Significantly, CS-23 exerted a synergistic effect with 32-fold reduction of the MIC of meropenem against NDM-1-expressing E. coli bacteria.

Keywords

3-formyl chromone; Covalent inhibitors; New Delhi Metallo-beta-lactamase-1 (NDM-1); Superbug.

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