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May 18, 2026Journal of Medicinal Chemistry0 citations

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

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WLWandong LiuQingdao National Laboratory for Marine Science and TechnologyCLChenyu LiuHong Kong Polytechnic UniversityYGY C GuoJilin University

Key Points

  • The study aims to evaluate the effectiveness of cephalexin-derived covalent inhibitors in reversing meropenem resistance mediated by NDM-1.
  • Evaluated interaction between selenazolone warhead and Cys208 at the NDM-1 active site.
  • Analyzed enzyme inhibition and stability of formed Se-S bond.
  • Identified potential therapeutic strategies against metallo-β-lactamases.
  • Covalent inhibitors formed a stable Se-S bond with Cys208, ensuring prolonged target engagement.
  • Demonstrated significant enzyme inhibition resulting in reversed meropenem resistance.
  • Identified cephalexin scaffold as a promising platform for developing NDM-1 inhibitors.

Abstract

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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Cite This Study

Liu et al. (2026) studied this question.

synapsesocial.com/papers/6a0aac2b5ba8ef6d83b6fc25https://doi.org/10.1021/acs.jmedchem.6c00314
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