Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries

Dmitriy Minond, S. Adrian Saldanha, Prem Subramaniam, Michael Spaargaren, Timothy Spicer, Joseph R. Fotsing, Timo Weide, Valery V. Fokin, K. Barry Sharpless, Moreno Galleni, Carine Bebrone, Patricia Lassaux, Peter Hodder

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37 Citations (Scopus)

Abstract

VIM-2 is an Ambler class B metallo-β-lactamase (MBL) capable of hydrolyzing a broad-spectrum of β-lactam antibiotics. Although the discovery and development of MBL inhibitors continue to be an area of active research, an array of potent, small molecule inhibitors is yet to be fully characterized for VIM-2. In the presented research, a compound library screening approach was used to identify and characterize VIM-2 inhibitors from a library of pharmacologically active compounds as well as a focused 'click' chemistry library. The four most potent VIM-2 inhibitors resulting from a VIM-2 screen were characterized by kinetic studies in order to determine Ki and mechanism of enzyme inhibition. As a result, two previously described pharmacologic agents, mitoxantrone (1,4-dihydroxy-5,8-bis([2-([2-hydroxyethyl]amino)ethyl]amino)-9,10-anthr acenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (Ki =Ki = 1.5 ± 0.2 μM) and the latter as a slowly reversible or irreversible inhibitor. Additionally, two novel sulfonyl-triazole analogs from the click library were identified as potent, competitive VIM-2 inhibitors: N-((4-((but-3-ynyloxy)methyl)-1H-1,2,3-triazol-5-yl)methyl)-4-iodobenzen esulfonamide (1, Ki = 0.41 ± 0.03 μM) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfona mide (2, Ki = 1.4 ± 0.10 μM). Mitoxantrone and pCMB were also found to potentiate imipenem efficacy in MIC and synergy assays employing Escherichia coli. Taken together, all four compounds represent useful chemical probes to further investigate mechanisms of VIM-2 inhibition in biochemical and microbiology-based assays.

Original languageEnglish
Pages (from-to)5027-5037
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number14
DOIs
Publication statusPublished - 15 Jul 2009
Externally publishedYes

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Keywords

  • β-Lactamase
  • Inhibitors
  • VIM-2

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Minond, D., Saldanha, S. A., Subramaniam, P., Spaargaren, M., Spicer, T., Fotsing, J. R., Weide, T., Fokin, V. V., Sharpless, K. B., Galleni, M., Bebrone, C., Lassaux, P., & Hodder, P. (2009). Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries. Bioorganic and Medicinal Chemistry, 17(14), 5027-5037. https://doi.org/10.1016/j.bmc.2009.05.070