IMB-XH1作为新型新德里金属-β-内酰胺酶-1(NDM-1)抑制剂的研究

doi:10.5246/jcps.2019.04.024

中国药学(英文版) ›› 2019, Vol. 28 ›› Issue (4): 238-246.DOI: 10.5246/jcps.2019.04.024

IMB-XH1作为新型新德里金属-β-内酰胺酶-1(NDM-1)抑制剂的研究

韩江雪¹, 肖春玲¹, 甘茂罗¹, 李兴华¹, 王颖¹, 郑佳音², 李东升¹, 刘琛楠¹, 关艳¹, 蒙建州¹, 黄树超¹, 刘忆霜^1*

1. 中国医学科学院北京协和医学院医药生物技术研究所, 国家新药(微生物)筛选实验室, 北京 100050
2. 首都医科大学神经生物学系, 北京 100069

收稿日期:2019-02-11 修回日期:2019-03-11 出版日期:2019-04-30 发布日期:2019-03-14
通讯作者: Tel.: +86-010-63020226, E-mail: rememberfrost@163.com
基金资助:
Natural Sciences Foundation of China (NSFC, Grant No. 81872913), the CAMS Initiative for Innovative Medicine (Grant No.2016-I2M-1-013), the Fundamental Research Funds for Central Public-interest Scientific Institution (Centre for Tuberculosis) (Grant No. 2016ZX310183-3) and the National High-tech R&D Program (863 Program, Grant No. 2015AA020911).

IMB-XH1 identified as a novel inhibitor of New Delhi metallo-β-lactamase-1

Jiangxue Han¹, Chunling Xiao¹, Maoluo Gan¹, Xinghua Li¹, Ying Wang¹, Jiayin Zheng², Dongsheng Li¹, Chennan Liu¹, Yan Guan¹, Jianzhou Meng¹, Shuchao Huang¹, Yishuang Liu^1*

1. National Key Laboratory for Screening New Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
2. Department of Neurobiology, Capital Medical University, Beijing 100069, China

Received:2019-02-11 Revised:2019-03-11 Online:2019-04-30 Published:2019-03-14
Contact: Tel.: +86-010-63020226, E-mail: rememberfrost@163.com
Supported by:
Natural Sciences Foundation of China (NSFC, Grant No. 81872913), the CAMS Initiative for Innovative Medicine (Grant No.2016-I2M-1-013), the Fundamental Research Funds for Central Public-interest Scientific Institution (Centre for Tuberculosis) (Grant No. 2016ZX310183-3) and the National High-tech R&D Program (863 Program, Grant No. 2015AA020911).

摘要/Abstract

摘要：

革兰氏阴性菌的耐药问题日益严峻, 已经引起了公众的广泛关注。产新德里金属β-内酰胺酶(NDM-1)的“超级细菌”对几乎所有的β-内酰胺类抗生素耐药。然而临床现有的β-内酰胺酶抑制剂对NDM-1等金属β-内酰胺酶无效, 因此, 临床上迫切需要有效NDM-1抑制剂。在这项研究中, 优化了NDM-1抑制剂的高通量筛选模型。应用该模型筛选NDM-1抑制剂, 并从不同来源的化合物样品中筛选得到一种NDM-1的抑制剂IMB-XH1。研究发现IMB-XH1与β-内酰胺类抗生素联合使用可以提高表达NDM-1的大肠埃希菌E.coli BL21(DE3)(pET-30a(+)-NDM-1)对β-内酰胺类抗生素的敏感性。酶促动力学研究表明IMB-XH1是NDM-1的非竞争性抑制剂。IMB-XH1还具有对其他金属β-内酰胺酶的抑制活性, 如IMP-4, ImiS和L1。IMB-XH1作为一种新型的NDM-1抑制剂, 值得进一步对其活性评价和作用机制进行深入研究。

关键词: NDM-1, 金属-β-内酰胺酶抑制剂, 高通量筛选, 细菌耐药

Abstract:

The problem of drug resistance of Gram-negative bacteria has become increasingly serious and has aroused widespread public concern. The “super bacteria” producing New Delhi metallo-beta-lactamase (NDM-1) are resistant to almost all β-lactam antibiotics. However, clinically existing β-lactamase inhibitors are ineffective against metallo-β-lactamases (MBLs) including NDM-1. Therefore, effective NDM-1 inhibitors are urgently needed. In this study, a high-throughput screening model for NDM-1inhibitors was optimized and used to screen NDM-1 inhibitors. As a result, IMB-XH1 was screened out as a novel NDM-1 inhibitor from 52 100 compounds of different sources. The combined use of IMB-XH1 can increase the sensitivity of E. coli BL21(DE3) (pET-30a(+)-NDM-1) to β-lactam antibiotics. Enzymatic kinetic studies indicate that IMB-XH1 is a non-competitive inhibitor of NDM-1 and also has inhibitory activity against other MBLs such as IMP-4, ImiS and L1. As a novel NDM-1 inhibitor, its activity and mechanism of action need to be further explored.

Key words: NDM-1, Metallo-β-lactamases inhibitor, High throughput screening, Bacterial resistance

中图分类号:

R962

Supporting:

韩江雪, 肖春玲, 甘茂罗, 李兴华, 王颖, 郑佳音, 李东升, 刘琛楠, 关艳, 蒙建州, 黄树超, 刘忆霜. IMB-XH1作为新型新德里金属-β-内酰胺酶-1(NDM-1)抑制剂的研究[J]. 中国药学(英文版), 2019, 28(4): 238-246.

Jiangxue Han, Chunling Xiao, Maoluo Gan, Xinghua Li, Ying Wang, Jiayin Zheng, Dongsheng Li, Chennan Liu, Yan Guan, Jianzhou Meng, Shuchao Huang, Yishuang Liu. IMB-XH1 identified as a novel inhibitor of New Delhi metallo-β-lactamase-1[J]. Journal of Chinese Pharmaceutical Sciences, 2019, 28(4): 238-246.

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IMB-XH1作为新型新德里金属-β-内酰胺酶-1(NDM-1)抑制剂的研究

IMB-XH1 identified as a novel inhibitor of New Delhi metallo-β-lactamase-1

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