Article (Scientific journals)
Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries
Minond, D.; Saldanha, S. A.; Spaargaren, M. et al.
2009In Bioorganic and Medicinal Chemistry, 17, p. 5027-37
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Keywords :
metallo-beta-lactamase; inhibitor
Abstract :
[en] VIM-2 is an Ambler class B metallo-beta-lactamase (MBL) capable of hydrolyzing a broad-spectrum of beta-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 K(i) 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-anthracenedione) and 4-chloromercuribenzoic acid (pCMB) were found to be active, the former as a non-competitive inhibitor (K(i)=K(i)(')=1.5+/-0.2microM) 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-iodobenzenesulfonamide (1, K(i)=0.41+/-0.03microM) and 4-iodo-N-((4-(methoxymethyl)-1H-1,2,3-triazol-5-yl)methyl)benzenesulfonamide (2, K(i)=1.4+/-0.10microM). 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Minond, D.;  The Scripps Research Institute > Lead Identification, Translational Research Institute
Saldanha, S. A.;  The Scripps Research Institute > Lead Identification, Translational Research Institute
Spaargaren, M.;  The Scripps Research Institute > Lead Identification, Translational Research Institute
Spicer, T.;  The Scripps Research Institute > Lead Identification, Translational Research Institute
Fotsing, J. R.;  The Scripps Research Institute > Department of Chemistry
Weide, T.;  The Scripps Research Institute > Department of Chemistry
Fokin, V. V.;  The Scripps Research Institute > Department of Chemistry
Sharpless, K. B.;  The Scripps Research Institute > Department of Chemistry and the Skaggs Institute for Chemical Biology
Galleni, Moreno ;  Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Bebrone, Carine ;  Université de Liège - ULiège > Centre d'ingénierie des protéines
Lassaux, Patricia ;  Université de Liège - ULiège > Doct. sc. (bioch., bioch. mol.&cell., bioinf.&mod.-Bologne)
Hodder, P.;  The Scripps Research Institute > Lead Identification, Translational Research Institute/ Department of Molecular Therapeutics
Language :
English
Title :
Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries
Publication date :
15 July 2009
Journal title :
Bioorganic and Medicinal Chemistry
ISSN :
0968-0896
eISSN :
1464-3391
Publisher :
Elsevier Science, Oxford, United Kingdom
Volume :
17
Pages :
5027-37
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 30 September 2009

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