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Identification of inhibitors of the antibiotic-resistance target New Delhi metallo-β-lactamase 1 by both nanoelectrospray ionization mass spectrometry and ultrafiltration liquid chromatography/mass spectrometry approaches.

Authors
  • Chen, Xin
  • Li, Lixin
  • Chen, Shuai
  • Xu, Yintong
  • Xia, Qiang
  • Guo, Yu
  • Liu, Xiang
  • Tang, Yanting
  • Zhang, Tanjie
  • Chen, Yue
  • Yang, Cheng
  • Shui, Wenqing
Type
Published Article
Journal
Analytical Chemistry
Publisher
American Chemical Society
Publication Date
Aug 20, 2013
Volume
85
Issue
16
Pages
7957–7965
Identifiers
DOI: 10.1021/ac401732d
PMID: 23863032
Source
Medline
License
Unknown

Abstract

Mass spectrometry-based platforms have gained increasing success in discovery of ligands bound to therapeutic targets as drug candidates. We established both a nanoelectrospray ionization mass spectrometry (nanoESI-MS) assay and an ultrafiltration liquid chromatography/mass spectrometry (LC/MS) assay to identify new ligands for New Delhi metallo-β-lactamase 1 (NDM-1), responsible for worldwide antibiotic resistance. To alleviate nonspecific binding of hydrophobic compounds and eliminate false positives typically encountered in the indirect LC/MS-based assay, we introduced a blocking protein in the control, which remarkably enhances the selectivity and accuracy of the indirect approach. Side-by-side comparison of the two MS-based approaches for the first time further reveals unique advantages of the indirect approach, including better reproducibility and tolerance of interference. Moreover, the success of fishing out a potent ligand from a mixture of small-molecule fragments demonstrates great potential of the indirect LC/MS-based approach for constructing a robust screening platform against combinatorial libraries or natural product extracts. More importantly, by combining the results of MS-based analyses, enzymatic activity assay, competition experiments, and structural simulation, we discovered a new compound as a promising drug candidate targeting NDM-1.

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