Structural and mechanistic insights into NDM-1 catalyzed hydrolysis of cephalosporins.
J Am Chem Soc
; 136(42): 14694-7, 2014 Oct 22.
Article
en En
| MEDLINE
| ID: mdl-25268575
ABSTRACT
Cephalosporins constitute a large class of ß-lactam antibiotics clinically used as antimicrobial drugs. New Dehli metallo-ß-lactamase (NDM-1) poses a global threat to human health as it confers on bacterial pathogen resistance to almost all ß-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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Beta-Lactamasas
/
Cefalosporinas
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Biocatálisis
Idioma:
En
Año:
2014
Tipo del documento:
Article