Investigation of synergistic antimicrobial effects of the drug combinations of meropenem and 1,2-benzisoselenazol-3(2H)-one derivatives on carbapenem-resistant Enterobacteriaceae producing NDM-1

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal

12 Scopus Citations
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Author(s)

  • Wen Bin Jin
  • Chen Xu
  • Qipeng Cheng
  • Xiao Lin Qi
  • Wei Gao
  • Zhiwei Zheng
  • Edward W.C. Chan
  • Yun-Chung Leung
  • Tak Hang Chan
  • Kwok-Yin Wong
  • Kin-Fai Chan

Detail(s)

Original languageEnglish
Pages (from-to)285-302
Journal / PublicationEuropean Journal of Medicinal Chemistry
Volume155
Online published6 Jun 2018
Publication statusPublished - 15 Jul 2018
Externally publishedYes

Abstract

The worldwide prevalence of NDM-1-producing bacteria has drastically undermined the clinical efficacy of the last line antibiotic of carbapenems, prompting a need to devise effective strategy to preserve their clinical value. Our previous studies have shown that ebselen can restore the efficacy of meropenem against a laboratory strain that produces NDM-1. Here we report the construction of a focused compound library of 1,2-benzisoselenazol-3(2H)-one derivatives which comprise a total of forty-six candidate compounds. The structure-activity relationship of these compounds and their potential to serve as an adjuvant to enhance the antimicrobial efficacy of meropenem against a collection of clinical NDM-1-producing carbapenem-resistant Enterobacteriaceae isolates was examined. Drug combination assays indicated that these derivatives exhibited synergistic antimicrobial activity when used along with meropenem, effectively restoring the activity of carbapenems against the resistant strains tested in a Galleria mellonella larvae in vivo infection model. The mode of inhibition of one compound, namely 11_a38, which was depicted when tested on the purified NDM-1 enzyme, indicated that it could covalently bind to the enzyme and displaced one zinc ion from the active site. Overall, this study provides a novel 1,2-benzisoselenazol-3(2H)-one scaffold that exhibits strong synergistic antimicrobial activity with carbapenems, and low cytotoxicity. The prospect of application of such compounds as carbapenem adjuvants warrants further evaluation.

Research Area(s)

  • Carbapenem adjuvants, Carbapenem-resistant Enterobacteriaceae, Drug combination, Ebselen derivatives, NDM-1 inhibitors, Synergistic activity

Citation Format(s)

Investigation of synergistic antimicrobial effects of the drug combinations of meropenem and 1,2-benzisoselenazol-3(2H)-one derivatives on carbapenem-resistant Enterobacteriaceae producing NDM-1. / Jin, Wen Bin; Xu, Chen; Cheng, Qipeng; Qi, Xiao Lin; Gao, Wei; Zheng, Zhiwei; Chan, Edward W.C.; Leung, Yun-Chung; Chan, Tak Hang; Wong, Kwok-Yin; Chen, Sheng; Chan, Kin-Fai.

In: European Journal of Medicinal Chemistry, Vol. 155, 15.07.2018, p. 285-302.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journal