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

doi:10.5246/jcps.2019.04.024

Journal of Chinese Pharmaceutical Sciences ›› 2019, Vol. 28 ›› Issue (4): 238-246.DOI: 10.5246/jcps.2019.04.024

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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).

Abstract

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

CLC Number:

R962

Supporting:

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

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