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. 2011 Jun 2;2(5):384–394. doi: 10.1007/s13238-011-1055-9

A structural view of the antibiotic degradation enzyme NDM-1 from a superbug

Yu Guo 1,3, Jing Wang 1,3, Guojun Niu 1,3, Wenqing Shui 1,3, Yuna Sun 4, Honggang Zhou 1,3, Yaozhou Zhang 1, Cheng Yang 1,3, Zhiyong Lou 2,✉, Zihe Rao 1,2,3,4,✉
PMCID: PMC4875342  PMID: 21637961

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.

Keywords: New Delhi metallo-β-lactamase 1 (NDM-1), drug resistance, crystal structure, drug discovery

Footnotes

These authors contributed equally to the work.

Contributor Information

Zhiyong Lou, Email: louzy@xtal.tsinghua.edu.cn.

Zihe Rao, Email: raozh@xtal.tsinghua.edu.cn.

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