The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29269938.
- Also identified by DOI 10.1038/s41467-017-02339-w and PMC identifier 5740130.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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, EI<sub>1</sub>, EI<sub>2</sub>, and EP, are trapped in these crystals. Our structural data reveal double-bond tautomerization from Δ<sup>2</sup> to Δ<sup>1</sup>, 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.
Medical subject headings
- Carbapenems
- Cephalosporins
- Penicillins
- beta-Lactamases