Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant

doi:10.1371/journal.pone.0023606

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	Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant
	Liang, Zhongjie 1; Li, Lianchun 1,2; Wang, Yuanyuan 1; Chen, Limin 1; Kong, Xiangqian 1; Hong, Yao 2; Lan, Lefu1 ; Zheng, Mingyue1 ; Cai Guang-Yang 1; Liu, Hong1
刊名	PLOS ONE
	2011-08-24
卷号	6 期号:8
ISSN号	1932-6203
DOI	10.1371/journal.pone.0023606
文献子类	Article
英文摘要	The New Delhi Metallo-beta-lactamase (NDM-1) was first reported in 2009 in a Swedish patient. A recent study reported that Klebsiella pneumonia NDM-1 positive strain or Escherichia coli NDM-1 positive strain was highly resistant to all antibiotics tested except tigecycline and colistin. These can no longer be relied on to treat infections and therefore, NDM-1 now becomes potentially a major global health threat. In this study, we performed modeling studies to obtain its 3D structure and NDM-1/antibiotics complex. It revealed that the hydrolytic mechanisms are highly conserved. In addition, the detailed analysis indicates that the more flexible and hydrophobic loop1, together with the evolution of more positive-charged loop2 leads to NDM-1 positive strain more potent and extensive in antibiotics resistance compared with other MBLs. Furthermore, through biological experiments, we revealed the molecular basis for antibiotics catalysis of NDM-1 on the enzymatic level. We found that NDM-1 enzyme was highly potent to degrade carbapenem antibiotics, while mostly susceptible to tigecycline, which had the ability to slow down the hydrolysis velocity of meropenem by NDM-1. Meanwhile, the mutagenesis experiments, including D124A, C208A, K211A and K211E, which displayed down-regulation on meropenem catalysis, proved the accuracy of our model. At present, there are no effective antibiotics against NDM-1 positive pathogen. Our study will provide clues to investigate the molecular basis of extended antibiotics resistance of NDM-1 and then accelerate the search for new antibiotics against NDM-1 positive strain in clinical studies.
资助项目	State Key Program of Basic Research of China[2009CB918502] ; State Key Program of Basic Research of China[2011CB510102] ; National Natural Science Foundation of China[20972174] ; National Natural Science Foundation of China[20720102040] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[91029704] ; Shanghai Committee of Science and Technology[10410703900] ; Shanghai Committee of Science and Technology[11ZR1444500] ; Shanghai Committee of Science and Technology[11XD1406100] ; Shanghai Committee of Science and Technology[09PJ1411600] ; Chinese Academy of Sciences[XDA01040305] ; Chinese Academy of Sciences[KSCX2-YW-R-143]
WOS关键词	METALLO-BETA-LACTAMASE ; 3-DIMENSIONAL STRUCTURE ; BACTEROIDES-FRAGILIS ; MECHANISM ; INHIBITION ; CATALYSIS
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000295832000037
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278432]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Liang, Zhongjie
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 200031, Peoples R China; 2.Shanghai Jiao Tong Univ, State Key Lab Med Genom, Shanghai Inst Hematol, Rui Jin Hosp,Sch Med, Shanghai 200030, Peoples R China; 3.Soochow Univ, Ctr Syst Biol, Suzhou, Jiangsu, Peoples R China; 4.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China
推荐引用方式 GB/T 7714	Liang, Zhongjie,Li, Lianchun,Wang, Yuanyuan,et al. Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant[J]. PLOS ONE,2011,6(8).
APA	Liang, Zhongjie.,Li, Lianchun.,Wang, Yuanyuan.,Chen, Limin.,Kong, Xiangqian.,...&Jiang, Hualiang.(2011).Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant.PLOS ONE,6(8).
MLA	Liang, Zhongjie,et al."Molecular Basis of NDM-1, a New Antibiotic Resistance Determinant".PLOS ONE 6.8(2011).