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

Han Feng, Xuehui Liu, Sheng Wang, Joy Fleming, Da-Cheng Wang () and Wei Liu ()
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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
Da-Cheng Wang: Chinese Academy of Sciences
Wei Liu: The Third Military Medical University

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02339-w

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