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


ABSTRACT: New Delhi metallo-?-lactamases (NDMs), the recent additions to metallo-?-lactamases (MBLs), pose a serious public health threat due to its highly efficient hydrolysis of ?-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 ?2 to ?1, absence of a bridging water molecule and an exclusive ?-diastereomeric product, all suggesting that the hydrolytic intermediates are protonated by a bulky water molecule incoming from the ?-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.

SUBMITTER: Feng H 

PROVIDER: S-EPMC5740130 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Feng Han H   Liu Xuehui X   Wang Sheng S   Fleming Joy J   Wang Da-Cheng DC   Liu Wei W  

Nature communications 20171221 1


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 mero  ...[more]

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