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J Am Chem Soc. 2014 Oct 22;136(42):14694-7. doi: 10.1021/ja508388e. Epub 2014 Oct 7.

Structural and mechanistic insights into NDM-1 catalyzed hydrolysis of cephalosporins.

Author information

1
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences , Beijing 100101, China.

Abstract

Cephalosporins constitute a large class of β-lactam antibiotics clinically used as antimicrobial drugs. New Dehli metallo-β-lactamase (NDM-1) poses a global threat to human health as it confers on bacterial pathogen resistance to almost all β-lactams, including penicillins, cephalosporins, and carbapenems. Here we report the first crystal structures of NDM-1 in complex with cefuroxime and cephalexin, as well as NMR spectra monitoring cefuroxime and cefixime hydrolysis catalyzed by NDM-1. Surprisingly, cephalosporoate intermediates were captured in both crystal structures determined at 1.3 and 2.0 Å. These results provide detailed information concerning the mechanism and pathways of cephalosporin hydrolysis. We also present the crystal structure and enzyme assays of a D124N mutant, which reveals that D124 most likely plays a more structural than catalytic role.

PMID:
25268575
DOI:
10.1021/ja508388e
[Indexed for MEDLINE]

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