A structural view of the antibiotic degradation enzyme NDM-1 from a superbug.
10.1007/s13238-011-1055-9
- Author:
Yu GUO
1
;
Jing WANG
;
Guojun NIU
;
Wenqing SHUI
;
Yuna SUN
;
Honggang ZHOU
;
Yaozhou ZHANG
;
Cheng YANG
;
Zhiyong LOU
;
Zihe RAO
Author Information
1. High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biotechnology and Medicine, Tianjin, China.
- Publication Type:Journal Article
- MeSH:
Amino Acid Sequence;
Anti-Bacterial Agents;
metabolism;
Binding Sites;
Captopril;
chemistry;
pharmacology;
Catalytic Domain;
Crystallography, X-Ray;
Drug Resistance, Bacterial;
Enterobacteriaceae;
enzymology;
Molecular Sequence Data;
Sequence Alignment;
Sequence Homology, Amino Acid;
beta-Lactamases;
chemistry;
metabolism
- From:
Protein & Cell
2011;2(5):384-394
- CountryChina
- Language:English
-
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.
