Summary of the probe development effort to identify inhibitors of AddAB recombination protein complex
Name: Summary of the probe development effort to identify inhibitors of AddAB recombination protein complex. ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Gerald R. Smith, Fred Hutchinson Cancer Research Center
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number: GM031693
Grant Proposal PI: Gerald R. Smith
External Assay ID: ADDAB_INH_SUMMARY
Name: Summary of the probe development effort to identify inhibitors of AddAB recombination protein complex.
Helicobacter pylori infects approximately half of the world's population and is responsible for inducing chronic gastric inflammation that can progress to gastric cancer (1). At the cellular level, Helicobacter pylori infection of the human stomach is associated with inflammation that elicits DNA damage in both bacterial and host cells (2). This DNA damage must be repaired in order for the bacteria to persist. The H. pylori AddAB helicase-exonuclease is required for DNA repair and efficient stomach colonization (3), and inhibitors of this enzyme may be useful antibacterial drugs for treating these infections. The AddAB class of enzymes is closely related to the RecBCD class of helicase-nucleases; both classes are widely distributed in bacteria but appear to be absent in eukaryotes (4). The protein complex functions in DNA repair by directing free DNA ends into the homologous recombination pathway (5). As a result, the identification of inhibitors of AddAB may be useful tools for elucidating the role of AddAB and RecBCD in bacterial recombination and as potential novel antibiotics with few off-target effects.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of ADDAB inhibitors. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. J Clin Invest. 2007 Jan;117(1):60-9.
2. Ernst P. Aliment Pharmacol Ther. 1999 Mar;13 Suppl 1:13-8. Review article: the role of inflammation in the pathogenesis of gastric cancer.
3. Dillingham MS, Kowalczykowski SC. RecBCD enzyme and the repair of double-stranded DNA breaks. Microbiol Mol Biol Rev. 2008 Dec;72(4):642-71.
4. Amundsen SK, Fero J, Hansen LM, Cromie GA, Solnick JV, Smith GR, Salama NR, Helicobacter pylori AddAB helicase-nuclease and RecA promote recombination-related DNA repair and survival during stomach colonization. Mol Microbiol, 2008. 69(4): p. 994-1007.
5. Chedin F. and Kowalczykowski S.C. A novel family of regulated helicases/nucleases from Gram-positive bacteria: insights into the initiation of DNA recombination, Mol. Microbiol. 43 (2002), pp. 823-834.
Summary, Summary AID, helicase, nuclease, exonuclease, ATP-dependent nuclease, AddAB, ADDAB, AddAB complex, RecBCD enzyme, beta subunit, gamma chain, alpha chain, Escherichia coli, E. coli, bacteria, Helicobacter pylori, phage, T4, DNA, dsDNA, DNA damage, DNA repair, DNA binding, ATP-binding, homologous recombination, recombination, Chi, inhibition, inhibitor, optical density, OD, absorbance, HTS, high throughput screen, primary, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML328
PubChem Substance ID (SID) for probe 1: 144186606
PubChem Compound ID (CID) for probe 1: 1517823
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 1000
Target for probe 1: AddAB; RecBCD (gi: 15645703,15646160)
Disease relevance for probe 1: Bacterial Infection
Anti-target for probe 1: E. Coli V66 Viability
Fold selectivity for probe 1: 34
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK148492/ (ID: 3040622)
Grant number for probe 1: GM031693
PubMed Publication ID (PMID) for probe 1: 22443934
NCBI Book chapter title for probe 1: ML328: A Novel Dual Inhibitor of Bacterial AddAB and RecBCD Helicase-nuclease DNA Repair Enzymes