Bookmark and Share
BioAssay: AID 1854

Summary of probe development efforts to identify selective inhibitors of VIM-2 metallo-beta-lactamase

Name: Summary of probe development efforts to identify selective inhibitors of VIM-2 metallo-beta-lactamase ..more
_
   
 Tested Compounds
 Tested Compounds
All(1)
 
 
Probe(1)
 
 
Active(1)
 
 
 Tested Substances
 Tested Substances
All(1)
 
 
Probe(1)
 
 
Active(1)
 
 
AID: 1854
Data Source: The Scripps Research Institute Molecular Screening Center (VIM-2SELECTIVE_INH_LEADS_SUMMARY)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-07-09
Modify Date: 2013-01-04

Data Table ( Complete ):           View Active Data    View All Data
Target
BioActive Compound: Chemical Probe: 1    Active: 1
Related Experiments
Show more
AIDNameTypeProbeComment
1527Primary biochemical high throughput screening assay to identify inhibitors of VIM-2 metallo-beta-lactamaseScreening depositor-specified cross reference: Primary screen (VIM-2 inhibitors in singlicate)
1856Epi-absorbance-based counterscreen for selective VIM-2 inhibitors: biochemical high throughput screening assay to identify inhibitors of IMP-1 metallo-beta-lactamase.Screening depositor-specified cross reference: Counterscreen (IMP-1 inhibitors in triplicate)
1857FRET-based counterscreen assay for selective VIM-2 inhibitors: biochemical high throughput screening assay to identify epi-absorbance assay artifactsScreening depositor-specified cross reference: Counterscreen (VIM-2 inhibitors in triplicate)
1860Epi-absorbance-based confirmation biochemical high throughput screening assay to identify selective inhibitors of VIM-2 metallo-beta-lactamase.Screening depositor-specified cross reference: Confirmation screen (VIM-2 inhibitors in triplicate)
1866Epi-absorbance-based counterscreen assay for selective VIM-2 inhibitors: biochemical high throughput screening assay to identify inhibitors of TEM-1 serine-beta-lactamase.Screening depositor-specified cross reference: Counterscreen (TEM-1 inhibitors in triplicate)
1919Epi-absorbance-based dose response biochemical high throughput screening assay for selective inhibitors of VIM-2 metallo-beta-lactamaseConfirmatory depositor-specified cross reference: Dose response (VIM-2 inhibitors in triplicate)
1920Epi-absorbance-based counterscreen for selective VIM-2 inhibitors: dose response biochemical high throughput screening assay to identify inhibitors of IMP-1 metallo-beta-lactamase.Confirmatory depositor-specified cross reference: Dose response counterscreen (IMP-1 inhibitors in triplicate)
1925Epi-absorbance-based counterscreen for selective VIM-2 inhibitors: dose response biochemical high throughput screening assay to identify inhibitors of TEM-1 serine-beta-lactamase.Confirmatory depositor-specified cross reference: Dose response counterscreen (TEM-1 inhibitors in triplicate)
1926FRET-based counterscreen for selective VIM-2 inhibitors: dose response biochemical high throughput screening assay to identify epi-absorbance assay artifacts.Confirmatory depositor-specified cross reference: Dose response counterscreen (VIM-2 inhibitors in triplicate)
1927FRET-based counterscreen for selective VIM-2 inhibitors: dose response biochemical high throughput screening assay to identify inhibitors of IMP-1 metallo-beta-lactamase.Confirmatory depositor-specified cross reference: Dose response counterscreen (IMP-1 inhibitors in triplicate)
2128Late stage results from the probe development efforts to identify selective inhibitors of VIM-2 metallo-beta-lactamase: probe resultsOther depositor-specified cross reference: Late stage results (VIM-2 inhibitors)
2184Epi-absorbance-based counterscreen assay for common VIM-2 and IMP-1 inhibitors: biochemical high throughput screening assay to identify inhibitors of TEM-1 serine-beta-lactamase.Screening depositor-specified cross reference: Counterscreen (TEM-1 inhibitors in triplicate)
2187Epi-absorbance-based confirmation assay for common VIM-2 and IMP-1 inhibitors: biochemical high throughput screening assay to identify inhibitors of VIM-2 metallo-beta-lactamase.Screening depositor-specified cross reference: Confirmation screen (VIM-2 inhibitors in triplicate)
2189Epi-absorbance-based confirmation assay for common IMP-1 and VIM-2 inhibitors: biochemical high throughput screening assay to identify inhibitors of IMP-1 metallo-beta-lactamase.Screening depositor-specified cross reference: Confirmation screen (IMP-1 inhibitors in triplicate)
2317Late stage results from the probe development efforts to identify selective inhibitors of VIM-2 metallo-beta-lactamase: Prior art resultsScreening depositor-specified cross reference: Prior art assays (VIM-2 inhibitors)
2319Late stage results from the probe development efforts to identify selective inhibitors of VIM-2 metallo-beta-lactamase: probe resultsOther depositor-specified cross reference: Revoked, data were merged into assay 2128.
2715Summary of probe development efforts to identify common inhibitors of VIM-2 and IMP-1 metallo-beta-lactamases (IMP-1 inhibitors)Summary depositor-specified cross reference: Summary (VIM-2 and IMP-1 common inhibitors)
2754Epi-absorbance-based dose response assay for common IMP-1 and VIM-2 inhibitors: biochemical high throughput screening assay to identify inhibitors of VIM-2 metallo-beta-lactamaseConfirmatory depositor-specified cross reference: Dose response (VIM-2 inhibitors in triplicate)
2755Epi-absorbance-based dose response assay for common IMP-1 and VIM-2 inhibitors: biochemical high throughput counterscreen to identify inhibitors of TEM-1 metallo-beta-lactamaseConfirmatory depositor-specified cross reference: Dose response counterscreen (TEM-1 inhibitors in triplicate)
2756Epi-absorbance-based dose response assay for common IMP-1 and VIM-2 inhibitors: biochemical high throughput screening assay to identify inhibitors of IMP-1metallo-beta-lactamaseConfirmatory depositor-specified cross reference: Dose response assay (IMP-1 inhibitors in triplicate)
2767Late stage counterscreen results from the probe development effort to identify common IMP-1 and VIM-2 inhibitors: Epi-absorbance-based biochemical dose response assay for inhibitors of TEM-1 metallo-beta-lactamaseConfirmatory depositor-specified cross reference: Late stage dose response counterscreen (TEM-1 inhibitors in triplicat)
2768Late stage results from the probe development effort to identify common IMP-1 and VIM-2 inhibitors: Epi-absorbance-based biochemical dose response assay for inhibitors of IMP-1metallo-beta-lactamaseConfirmatory depositor-specified cross reference: Late stage dose response (IMP-1 inhibitors in triplicate)
2769Late stage results from the probe development effort to identify common IMP-1 and VIM-2 inhibitors: Epi-absorbance-based biochemical dose response assay for inhibitors of VIM-2 metallo-beta-lactamaseConfirmatory depositor-specified cross reference: Late stage dose response (VIM-2 inhibitors in triplicate)
449774Late stage counterscreen results from the probe development efforts to identify common IMP-1 and VIM-2 inhibitors: wildtype E. coli growth inhibition dose response assay (MIC: minimum inhibitory concentration)Other depositor-specified cross reference: Late stage dose response counterscreen (wildtype E. coli growth inhibition in triplicate)
463099Late stage assay provider counterscreen results from the probe development efforts to identify common IMP-1 and VIM-2 inhibitors: IMP1-transformed E. coli growth inhibition dose response assay in the presence of imipenemOther depositor-specified cross reference: Late stage dose response counterscreen (IMP1-transformed E. coli growth inhibition in the presence o
463100Late stage assay provider counterscreen results from the probe development efforts to identify common IMP-1 and VIM-2 inhibitors: VIM-2-transformed E. coli growth inhibition dose response assay in the presence of imipenemOther depositor-specified cross reference: Late stage dose response counterscreen (VIM2-transformed E. coli growth inhibition in the presence o
504620Late stage assay provider results from the probe development efforts to identify selective inhibitors of VIM-2 metallo-beta-lactamase: VIM-2-transformed E. coli growth inhibition in the presence of imipenem (synergy)Confirmatory depositor-specified cross reference: Late stage assay (VIM-2-transformed E. coli growth inhibitors in the presence of imipenem (synergy))
624079Late stage assay provider results from the probe development efforts to identify nonselective inhibitors of VIM-2 metallo-beta-lactamase: Absorbance-based biochemical assays to determine the ability of probe candidates and selected analogs to inhibit VIM-2Confirmatory1 depositor-specified cross reference: Late stage dose response (VIM-2 inhibition by probe candidates and selected analogs)
624080Late stage assay provider results from the probe development efforts to identify inhibitors of VIM-2 metallo-beta-lactamase (nonselective): Growth inhibition of clinically relevant VIM-2 transformed P. aeruginosa (PA641) in the presence of imipenem (synergy)Other depositor-specified cross reference: Late stage assay (VIM-2 transformed P. aeruginosa (PA641) growth inhibitors in the presence of imipe
624081Late stage assay provider results from the probe development efforts to identify inhibitors of VIM-2 metallo-beta-lactamase (nonselective): VIM-2-transformed E. coli growth inhibition in the presence of imipenem (synergy)Other1 depositor-specified cross reference: Late stage assay (VIM-2-transformed E. coli growth inhibitors in the presence of imipenem (synergy))
624082Late stage assay provider results from the probe development efforts to identify inhibitors of VIM-2 metallo-beta-lactamase (nonselective): Growth inhibition of clinically relevant New Delhi metallo-beta-lactamase-1 (NDM-1)-transformed K. pneumoniae (BAA-2146) in the presence of imipenem (synergy)Other depositor-specified cross reference: Late stage assay (NDM-1 transformed K. pneumoniae (BAA-2146) growth inhibitors in the presence of im
624083Late stage assay provider results from the probe development efforts to identify nonselective inhibitors of VIM-2 metallo-beta-lactamase: Absorbance-based biochemical assays to determine the ability of probe candidates and selected analogs to inhibit VIM-2Confirmatory1 depositor-specified cross reference: Late stage dose response (VIM-2 inhibition by probe candidates and selected analogs)
624084Late stage assay provider results from the probe development efforts to identify nonselective inhibitors of VIM-2 metallo-beta-lactamase: Absorbance-based biochemical assays to determine the ability of probe candidates and selected analogs to inhibit IMP-1Confirmatory1 depositor-specified cross reference: Late stage dose response (IMP-1 inhibition by probe candidates and selected analogs)
624085Late stage assay provider results from the probe development efforts to identify nonselective inhibitors of VIM-2 metallo-beta-lactamase: Absorbance-based biochemical assays to determine the ability of probe candidates and selected analogs to inhibit IMP-1Confirmatory1 depositor-specified cross reference: Late stage dose response (IMP-1 inhibition by probe candidates and selected analogs)
624090Late stage assay provider results from the probe development efforts to identify nonselective inhibitors of VIM-2 metallo-beta-lactamase: Absorbance-based biochemical assays to determine the ability of probe candidates and selected analogs to inhibit AmpCConfirmatory depositor-specified cross reference: Late stage dose response (AmpC inhibition by probe candidates and selected analogs)
624092Late stage assay provider results from the probe development efforts to identify nonselective inhibitors of VIM-2 metallo-beta-lactamase: Absorbance-based biochemical assays to determine the ability of probe candidates and selected analogs to inhibit TEM-1Confirmatory depositor-specified cross reference: Late stage dose response (TEM-1 inhibition by probe candidates and selected analogs)
624095Late stage assay provider results from the probe development efforts to identify inhibitors of VIM-2 metallo-beta-lactamase (nonselective): Growth inhibition of clinically relevant IMP-1 transformed P. aeruginosa (KN20) in the presence of imipenem (synergy)Other depositor-specified cross reference: Late stage assay (IMP-1 transformed P. aeruginosa (KN20) growth inhibitors in the presence of imipen
624096Late stage assay provider results from the probe development efforts to identify inhibitors of VIM-2 metallo-beta-lactamase (nonselective): Growth inhibition of clinically relevant VIM-2-transformed Acinetobacter species (YMC07/8/B3323) in the presence of imipenem (synergy)Other2 depositor-specified cross reference: Late stage assay (VIM-2-transformed Acinetobacter species (YMC07/8/B3323) growth inhibitors in the p
624097Late stage assay provider results from the probe development efforts to identify inhibitors of VIM-2 metallo-beta-lactamase (nonselective):IMP-1-transformed E. coli growth inhibition in the presence of imipenem (synergy)Other1 depositor-specified cross reference: Late stage assay (IMP-1-transformed E. coli growth growth inhibitors in the presence of imipenem (sy
1556Epi-absorbance primary biochemical high throughput screening assay to identify inhibitors of IMP-1 metallo-beta-lactamaseScreening same project related to Summary assay
Description:
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Center Affiliation: The Scripps Research Institute (TSRI)
Assay Provider: Peter Hodder, TSRI
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R21 NS059451-01 Fast Track
Grant Proposal PI: Peter Hodder, TSRI
External Assay ID: VIM-2SELECTIVE_INH_LEADS_SUMMARY

Name: Summary of probe development efforts to identify selective inhibitors of VIM-2 metallo-beta-lactamase

Description:

The emergence of gram-negative bacteria that exhibit multi-drug resistance, combined with the paucity of new antibiotics, poses a public health challenge (1). The production of bacterial beta-lactamase enzymes, in particular, is a common mechanism of drug resistance (2-4). The beta-lactamases evolved from bacteria with resistance to naturally-occurring beta-lactams or penams (5), agents which inhibit the transpeptidase involved in cell wall biosynthesis (6). Human medicine adapted these agents into synthetic antibiotics such as penicillins, cephalosporins, carbapenems, and monobactams that contain a 2-azetidone ring (5, 7). The metallo-beta-lactamases (MBL) are zinc-dependent class B beta-lactamases that hydrolyze the beta-lactam ring, rendering the antibiotic ineffective (6, 8). Increasingly, nosocomial beta-lactam antibiotic resistance arises in P. aeruginosa, Enterobacteriaceae, and other pathogenic bacteria via gene transfer of B1 MBLs (4, 9), including IMP (active on IMiPenem) (10) and VIM (Verona IMipenemase) (11, 12). For two of these enzymes, VIM-2 and IMP-1, no inhibitors exist for clinical use (6, 9). Thus, the identification of MBL inhibitors would provide useful tools for reducing nosocomial infections and elucidating their mechanism of action (13).

Summary of Probe Development Effort:

Following primary HTS in singlicate to identify selective VIM-2 inhibitors (AID 1527) and counterscreening in singlicate against the IMP-1 metallo-beta-lactamase (AID 1556), certain compounds were identified as possible candidates for probe development. These compounds were tested in a confirmation assay (AID 1860) and a dose response assay (AID 1919). They were then tested in counterscreen and dose response assays for IMP-1 inhibitors (AIDs 1856, 1920, and 1927), VIM-2 (CCF2) inhibitors (AIDs 1857 and 1926), and TEM-1 inhibitors (AIDs 1866 and 1925).

The above probe development effort resulted in the identification of one probe (AID 2128). A probe report has been published (http://mlpcn.florida.scripps.edu/index.php/probes/probe-reports.html). A probe report for SID 85856282 can be found in the Molecular Libraries Bookshelf (PubMed Books)(http://www.ncbi.nlm.nih.gov/books) under ML121.

References:

1. Siegel, R.E., Emerging gram-negative antibiotic resistance: daunting challenges, declining sensitivities, and dire consequences. Respir Care, 2008. 53(4): p. 471-9.
2. Gupta, V., An update on newer beta-lactamases. Indian J Med Res, 2007. 126(5): p. 417-27.
3. Bradford, P.A., Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin Microbiol Rev, 2001. 14(4): p. 933-51, table of contents.
4. Sacha, P., Wieczorek, P., Hauschild, T., Zorawski, M., Olszanska, D., and Tryniszewska, E., Metallo-beta-lactamases of Pseudomonas aeruginosa--a novel mechanism resistance to beta-lactam antibiotics. Folia Histochem Cytobiol, 2008. 46(2): p. 137-42.
5. Koch, A.L., Bacterial wall as target for attack: past, present, and future research. Clin Microbiol Rev, 2003. 16(4): p. 673-87.
6. Jin, W., Arakawa, Y., Yasuzawa, H., Taki, T., Hashiguchi, R., Mitsutani, K., Shoga, A., Yamaguchi, Y., Kurosaki, H., Shibata, N., Ohta, M., and Goto, M., Comparative study of the inhibition of metallo-beta-lactamases (IMP-1 and VIM-2) by thiol compounds that contain a hydrophobic group. Biol Pharm Bull, 2004. 27(6): p. 851-6.
7. Abeylath, S.C. and Turos, E., Drug delivery approaches to overcome bacterial resistance to beta-lactam antibiotics. Expert Opin Drug Deliv, 2008. 5(9): p. 931-49.
8. Wang, Z., Fast, W., Valentine, A.M., and Benkovic, S.J., Metallo-beta-lactamase: structure and mechanism. Curr Opin Chem Biol, 1999. 3(5): p. 614-22.
9. Walsh, T.R., Toleman, M.A., Poirel, L., and Nordmann, P., Metallo-beta-lactamases: the quiet before the storm? Clin Microbiol Rev, 2005. 18(2): p. 306-25.
10. Hirakata, Y., Izumikawa, K., Yamaguchi, T., Takemura, H., Tanaka, H., Yoshida, R., Matsuda, J., Nakano, M., Tomono, K., Maesaki, S., Kaku, M., Yamada, Y., Kamihira, S., and Kohno, S., Rapid detection and evaluation of clinical characteristics of emerging multiple-drug-resistant gram-negative rods carrying the metallo-beta-lactamase gene blaIMP. Antimicrob Agents Chemother, 1998. 42(8): p. 2006-11.
11. Lauretti, L., Riccio, M.L., Mazzariol, A., Cornaglia, G., Amicosante, G., Fontana, R., and Rossolini, G.M., Cloning and characterization of blaVIM, a new integron-borne metallo-beta-lactamase gene from a Pseudomonas aeruginosa clinical isolate. Antimicrob Agents Chemother, 1999. 43(7): p. 1584-90.
12. Wang, C.X. and Mi, Z.H., Imipenem-resistant Pseudomonas aeruginosa producing IMP-1 metallo-beta-lactamases and lacking the outer-membrane protein OprD. J Med Microbiol, 2006. 55(Pt 3): p. 353-4.
13. Zuck P, O'Donnell GT, Cassaday J, Chase P, Hodder P, Strulovici B, Ferrer M. Miniaturization of absorbance assays using the fluorescent properties of white microplates. Anal Biochem. 2005 Jul 15;342 (2):254-9.
14. Minond D, Saldanha SA, Subramaniam P, Spaargaren M, Spicer T, Fotsing JR, Weide T, Fokin VV,
Sharpless KB, Galleni M, Bebrone C, Lassaux P, Hodder P. Inhibitors of VIM-2 by screening pharmacologically active and click-chemistry compound libraries. Bioorg Med Chem. 2009 Jul 15;17(14):5027-37.

Keywords:

Summary AID, VIM-2, Probe, probes beta-lactamase, antibiotic resistance, bacteria, primary, confirmation, HTS, high throughput screen, 1536, selective, inhibitor, epi-absorbance, fluorescence, Scripps, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Center Network, MLPCN.
Protocol
Please see Related Bioassays for protocols performed in this probe development effort.
Comment
A probe has been identified.
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML #Unique alphanumeric identifier assigned to a chemical probe molecule within the Molecular Libraries Probe Production Centers Network (MLPCN).String
Additional Information
Grant Number: 1 R21 NS059451-01 Fast Track

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
PageFrom: