title: A structural view of the antibiotic degradation enzyme NDM-1 from a superbug.
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.
authors.affiliation: High-throughput Molecular Drug Discovery Center, Tianjin Joint Academy of Biotechnology and Medicine, Tianjin, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Guo
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Guojun
authors.initials: G
authors.lastname: Niu
authors.forename: Wenqing
authors.initials: W
authors.lastname: Shui
authors.forename: Yuna
authors.initials: Y
authors.lastname: Sun
authors.forename: Honggang
authors.initials: H
authors.lastname: Zhou
authors.forename: Yaozhou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Lou
authors.forename: Zihe
authors.initials: Z
authors.lastname: Rao
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001665:Binding Sites; D002216:Captopril / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D024881:Drug Resistance, Bacterial; D004755:Enterobacteriaceae / Q000201:enzymology; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D002216:Captopril; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1