期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 62, 期 11, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01579-18
关键词
microbial antibiotic resistance; metallo-beta-lactamase; NDM-1; conformational change; structure-based drug design
资金
- Natural Science Foundation of China [31670753]
- Guangdong Science and Technology Program [2017B030301018]
- Shenzhen Science and Technology Innovation Committee [JCYJ20160608140912962, ZDSYS20140509142721429]
- Health and Medical Research Fund of Hong Kong [15140992]
- Hong Kong RGC [C5026-16G, AoE/P-705/16]
- Natural Science Foundation of Guangdong Province [2016A030313053]
- Special Fund for Development of Strategic Emerging Industries in Shenzhen [JCYJ20160520174823939]
beta-Lactam antibiotics are the mainstay for the treatment of bacterial infections. However, elevated resistance to these antibiotics mediated by metallo-beta-lactamases (MBLs) has become a global concern. New Delhi metallo-beta-lactamase-1 (NDM-1), a newly added member of the MBL family that can hydrolyze almost all beta-lactam antibiotics, has rapidly spread all over the world and poses serious clinical threats. Broad-spectrum and mechanism-based inhibitors against all MBLs are highly desired, but the differential mechanisms of MBLs toward different antibiotics pose a great challenge. To facilitate the design of mechanism-based inhibitors, we investigated the active-site conformational changes of NDM-1 through the determination of a series of 15 high-resolution crystal structures in native form and in complex with products and by using biochemical and biophysical studies, site-directed mutagenesis, and molecular dynamics computation. The structural studies reveal the consistency of the active-site conformations in NDM-1/product complexes and the fluctuation in native NDM-1 structures. The enzymatic measurements indicate a correlation between enzymatic activity and the active-site fluctuation, with more fluctuation favoring higher activity. This correlation is further validated by structural and enzymatic studies of the Q123G mutant. Our combinational studies suggest that active-site conformational fluctuation promotes the enzymatic activity of NDM-1, which may guide further mechanism studies and inhibitor design.
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