A structural view of the antibiotic degradation enzyme NDM-1 from a superbug
Protein & Cell
;
(12): 384-394, 2011.
Artigo
em Inglês
| WPRIM
| ID: wpr-757087
ABSTRACT
Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are a type of newly discovered antibioticresistant bacteria. The rapid pandemic spread of NDM-1 bacteria worldwide (spreading to India, Pakistan, Europe, America, and Chinese Taiwan) in less than 2 months characterizes these microbes as a potentially major global health problem. The drug resistance of NDM-1 bacteria is largely due to plasmids containing the blaNDM-1 gene shuttling through bacterial populations. The NDM-1 enzyme encoded by the blaNDM-1 gene hydrolyzes β-lactam antibiotics, allowing the bacteria to escape the action of antibiotics. Although the biological functions and structural features of NDM-1 have been proposed according to results from functional and structural investigation of its homologues, the precise molecular characteristics and mechanism of action of NDM-1 have not been clarified. Here, we report the three-dimensional structure of NDM-1 with two catalytic zinc ions in its active site. Biological and mass spectroscopy results revealed that D-captopril can effectively inhibit the enzymatic activity of NDM-1 by binding to its active site with high binding affinity. The unique features concerning the primary sequence and structural conformation of the active site distinguish NDM-1 from other reported metallo-β-lactamases (MBLs) and implicate its role in wide spectrum drug resistance. We also discuss the molecular mechanism of NDM-1 action and its essential role in the pandemic of drug-resistant NDM-1 bacteria. Our results will provide helpful information for future drug discovery targeting drug resistance caused by NDM-1 and related metallo-β-lactamases.
Texto completo:
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Índice:
WPRIM (Pacífico Ocidental)
Assunto principal:
Farmacologia
/
Beta-Lactamases
/
Sítios de Ligação
/
Dados de Sequência Molecular
/
Captopril
/
Química
/
Alinhamento de Sequência
/
Sequência de Aminoácidos
/
Homologia de Sequência de Aminoácidos
/
Cristalografia por Raios X
Idioma:
Inglês
Revista:
Protein & Cell
Ano de publicação:
2011
Tipo de documento:
Artigo
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