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 language | English |
|---|---|
| Pages (from-to) | 5027-5037 |
| Number of pages | 11 |
| Journal | Bioorganic and Medicinal Chemistry |
| Volume | 17 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - 15 Jul 2009 |
| Externally published | Yes |
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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
Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries. / Minond, Dmitriy; Saldanha, S. Adrian; Subramaniam, Prem; Spaargaren, Michael; Spicer, Timothy; Fotsing, Joseph R.; Weide, Timo; Fokin, Valery V.; Sharpless, K. Barry; Galleni, Moreno; Bebrone, Carine; Lassaux, Patricia; Hodder, Peter.
In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 14, 15.07.2009, p. 5027-5037.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries
AU - Minond, Dmitriy
AU - Saldanha, S. Adrian
AU - Subramaniam, Prem
AU - Spaargaren, Michael
AU - Spicer, Timothy
AU - Fotsing, Joseph R.
AU - Weide, Timo
AU - Fokin, Valery V.
AU - Sharpless, K. Barry
AU - Galleni, Moreno
AU - Bebrone, Carine
AU - Lassaux, Patricia
AU - Hodder, Peter
PY - 2009/7/15
Y1 - 2009/7/15
N2 - 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.
AB - 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.
KW - β-Lactamase
KW - Inhibitors
KW - VIM-2
UR - http://www.scopus.com/inward/record.url?scp=67650227781&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67650227781&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2009.05.070
DO - 10.1016/j.bmc.2009.05.070
M3 - Article
C2 - 19553129
AN - SCOPUS:67650227781
VL - 17
SP - 5027
EP - 5037
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 14
ER -