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The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis

Author

Listed:
  • Han Feng

    (Chinese Academy of Sciences)

  • Xuehui Liu

    (Chinese Academy of Sciences)

  • Sheng Wang

    (Huazhong University of Science and Technology)

  • Joy Fleming

    (Chinese Academy of Sciences
    Foshan University)

  • Da-Cheng Wang

    (Chinese Academy of Sciences)

  • Wei Liu

    (The Third Military Medical University)

Abstract

New Delhi metallo-β-lactamases (NDMs), the recent additions to metallo-β-lactamases (MBLs), pose a serious public health threat due to its highly efficient hydrolysis of β-lactam antibiotics and rapid worldwide dissemination. The MBL-hydrolyzing mechanism for carbapenems is less studied than that of penicillins and cephalosporins. Here, we report crystal structures of NDM-1 in complex with hydrolyzed imipenem and meropenem, at resolutions of 1.80–2.32 Å, together with NMR spectra monitoring meropenem hydrolysis. Three enzyme-intermediate/product derivatives, EI1, EI2, and EP, are trapped in these crystals. Our structural data reveal double-bond tautomerization from Δ2 to Δ1, absence of a bridging water molecule and an exclusive β-diastereomeric product, all suggesting that the hydrolytic intermediates are protonated by a bulky water molecule incoming from the β-face. These results strongly suggest a distinct mechanism of NDM-1-catalyzed carbapenem hydrolysis from that of penicillin or cephalosporin hydrolysis, which may provide a novel rationale for design of mechanism-based inhibitors.

Suggested Citation

  • Han Feng & Xuehui Liu & Sheng Wang & Joy Fleming & Da-Cheng Wang & Wei Liu, 2017. "The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02339-w
    DOI: 10.1038/s41467-017-02339-w
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