一种新型NDM-1抑制剂: (–)-表儿茶素没食子酸酯

doi:10.5246/jcps.2021.09.059

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (9): 716-724.DOI: 10.5246/jcps.2021.09.059

一种新型NDM-1抑制剂: (–)-表儿茶素没食子酸酯

王倩, 刘琛楠, 韩江雪, 刘思含, 肖春玲, 关艳, 李兴华, 王颖, 王潇, 蒙建州, 甘茂罗, 刘忆霜^*()

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

收稿日期:2021-03-10 修回日期:2021-05-23 接受日期:2021-08-11 出版日期:2021-09-27 发布日期:2021-09-27
通讯作者: 刘忆霜
作者简介:
+ Tel.: +86-10-63020226, E-mail: liuys@imb.pumc.edu.cn
基金资助:
Natural Sciences Foundation of China (NSFC, Grant No. 81872913); National High-tech R&D Program (863 Program, Grant No. 2015AA020911).

(–)-Epicatechin gallate serves as a novel new delhi metallo-β-lactamase-1 (NDM-1) inhibitor

Qian Wang, Chennan Liu, Jiangxue Han, Sihan Liu, Chunling Xiao, Yan Guan, Xinghua Li, Ying Wang, Xiao Wang, Jianzhou Meng, Maoluo Gan, Yishuang Liu^*()

National Key Laboratory for Screening New Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

Received:2021-03-10 Revised:2021-05-23 Accepted:2021-08-11 Online:2021-09-27 Published:2021-09-27
Contact: Yishuang Liu

摘要/Abstract

摘要：

NDM-1导致的β-内酰胺类抗生素耐药问题已成为威胁全球公共卫生的重大危机。我们前期经筛选发现(–)-表儿茶素没食子酸酯是一种有效的NDM-1抑制剂, 本文进一步探讨了其抑制活性和作用方式。结果显示, (–)-表儿茶素没食子酸酯以一种可逆的、非竞争性的模式抑制NDM-1的活性, IC50值为4.48 μM。(–)-表儿茶素没食子酸酯能有效恢复多种β-内酰胺类抗生素对NDM-1菌的抑菌活性, 特别是对于碳青霉烯类抗生素有较显著的作用。锌离子回补实验结果提示, (–)-表儿茶素没食子酸酯发挥作用可能与对锌离子的影响有关, 然而不同于传统螯合剂, 它在体内外均展现出较低的毒性。综上所述, 我们的结果显示(–)-表儿茶素没食子酸酯能够协助碳青霉烯类抗生素抑制NDM-1产生菌, 是一种具有潜力的NDM-1抑制剂。

关键词: NDM-1, (–)-表儿茶素没食子酸酯, 抑制剂, 抗生素耐药

Abstract:

The β-lactam antibiotic resistance caused by NDM-1 has become a major crisis of global public health. We have previously screened out (–)-epicatechin gallate (ECG) as a potent NDM-1 inhibitor. We further discussed its inhibitory effect and action mode in the present study. According to our results, ECG reversibly inactivated NDM-1 in a non-competitive mode, with an IC₅₀ value of 4.48 μM. ECG effectively recovered the activity of several β-lactam antibiotics against resistant strain harboring blaNDM-1. Especially, the effects on carbapenems were worth mentioning. The zinc supplement assay indicated a zinc-related mechanism of ECG. Different from traditional chelating agents, it showed low toxicity both in vivo and in vitro. In a word, our findings provided a promising NDM-1 inhibitor, ECG, which was able to assist carbapenems against NDM-1-producing strain.

Key words: NDM-1, (–)-Epicatechin gallate, Inhibitor, Antibiotics resistance

Supporting:

王倩, 刘琛楠, 韩江雪, 刘思含, 肖春玲, 关艳, 李兴华, 王颖, 王潇, 蒙建州, 甘茂罗, 刘忆霜. 一种新型NDM-1抑制剂: (–)-表儿茶素没食子酸酯[J]. 中国药学(英文版), 2021, 30(9): 716-724.

Qian Wang, Chennan Liu, Jiangxue Han, Sihan Liu, Chunling Xiao, Yan Guan, Xinghua Li, Ying Wang, Xiao Wang, Jianzhou Meng, Maoluo Gan, Yishuang Liu. (–)-Epicatechin gallate serves as a novel new delhi metallo-β-lactamase-1 (NDM-1) inhibitor[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(9): 716-724.

图/表 5

Figure 1. ECG inhibits NDM-1 in a dose-dependent manner. (A) The chemical structure of ECG; (B) Determination of the IC50 value of ECG against NDM-1; (C) Reversibility assay; (D) Lineweaver-Burk plot to examine the inhibition model of ECG against NDM-1.

Figure 2. ECG interacts with NDM-1 of medium strength. (A) The fluorescence emission spectrum of NDM-1 with ECG; (B) SPR spectrum after adding ECG with gradient concentration.

Table 1. MICs of different β-lactams in combination with ECG against NDM-1-producing strain.

Figure 3. Microdilution checkerboard analysis of ECG and meropenem (A); and biapenem (B).

Figure 4. Supplement of exogenous zinc ion reverses the inhibitory effect of ECG on NDM-1.

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一种新型NDM-1抑制剂: (–)-表儿茶素没食子酸酯

(–)-Epicatechin gallate serves as a novel new delhi metallo-β-lactamase-1 (NDM-1) inhibitor

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