Journal
PROTEIN & CELL
Volume 2, Issue 5, Pages 384-394Publisher
OXFORD UNIV PRESS
DOI: 10.1007/s13238-011-1055-9
Keywords
New Delhi metallo-beta-lactamase 1 (NDM-1); drug resistance; crystal structure; drug discovery
Categories
Funding
- National Natural Science Foundation of China [30870486, 30730022]
- National Major Projects [2009ZX10004-804, 2009ZX09311-001, 2009ZX10004-304]
- National Basic Research Program (973 Program) [2011CB915501, 2011CB910304]
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Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-beta-lactamase 1 (NDM-1) are a type of newly discovered antibiotic-resistant 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 beta-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-beta-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-beta-lactamases.
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