Journal article
From bacterial genomes to novel antibacterial agents: discovery, characterization, and antibacterial activitv of compounds that bind to HI0065 (YjeE) from Haemophilus influenzae
Chemical biology & drug design, Vol.69(6), pp.395-404
06/01/2007
DOI: 10.1111/j.1747-0285.2007.00521.x
PMID: 17581233
Abstract
As part of a fully integrated and comprehensive strategy to discover novel antibacterial agents, NMR- and mass spectrometry-based affinity selection screens were performed to identify compounds that bind to protein targets uniquely found in bacteria and encoded by genes essential for microbial viability. A biphonyl acid lead series emerged from an NMR-based screen with the Haemophilus influenzae protein H10065, a member of a family of probable ATP-binding proteins found exclusively in eubacteria. The structure-activity relationships developed around the NMR-derived biphenyl acid lead were consistent with on-target antibacterial activity as the Staphylococcus aureus antibacterial activity of the series correlated extremely well with binding affinity to H10065, while the correlation of binding affinity with B-cell cytotoxicity was relatively poor. Although further studies are needed to conclusively establish the mode of action of the biphenyl series, these compounds represent novel leads that can serve as the basis for the development of novel antibacterial agents that appear to work via an unprecedented mechanism of action. Overall, these results support the genomics-driven hypothesis that targeting bacterial essential gone products that are not present in eukaryotic cells can identify novel antibacterial agents.
Details
- Title: Subtitle
- From bacterial genomes to novel antibacterial agents: discovery, characterization, and antibacterial activitv of compounds that bind to HI0065 (YjeE) from Haemophilus influenzae
- Creators
- Claude G. Lerner - Abbott (United States)Philip J. HajdukRolf Wagner - Abbott (United States)Frank L. Wagenaar - Abbott (United States)Charlotte Woodall - Abbott (United States)Yu-Gui GuXenia B. Searle - Abbott (United States)Alan S. Florjancic - Abbott (United States)Tianyuan Zhang - Abbott (United States)Richard F. Clark - Abbott (United States)Curt S. Cooper - Abbott (United States)Jamey C. Mack - Abbott (United States)Liping Yu - Abbott (United States)Mengli Cai - Abbott (United States)Steven F. Betz - Abbott (United States)Linda E. Chovan - Abbott (United States)J. Owen McCallCandace L. Black-SchaeferStephan J. Kakavas - Abbott (United States)Mark E. Schurdak - Abbott (United States)Kenneth M. Comess - Abbott (United States)Karl A. Walter - Abbott (United States)Rohinton Edalji - Abbott (United States)Sarah A. Dorwin - Abbott (United States)Richard A. Smith - Abbott (United States)Eric J. Hebert - Abbott (United States)John E. Harlan - Abbott (United States)Randy E. Metzger - Abbott (United States)Philip J. MartaJohn L. Baranowski - Abbott (United States)Michael L. Coen - Abbott (United States)Susan J. Thornewell - Abbott (United States)Annapur G. Shivakumar - Abbott (United States)Anne Y. Saiki - Abbott (United States)Niru Soni - Abbott (United States)Mai Bui - Abbott (United States)Darlene J. Balli - Abbott (United States)William J. Sanders - Abbott (United States)Angela M. Nilius - Abbott (United States)Thomas F. Holzman - Abbott (United States)Stephen W. Fesik - Abbott (United States)Bruce A. Beutel - Abbott (United States)
- Resource Type
- Journal article
- Publication Details
- Chemical biology & drug design, Vol.69(6), pp.395-404
- DOI
- 10.1111/j.1747-0285.2007.00521.x
- PMID
- 17581233
- NLM abbreviation
- Chem Biol Drug Des
- ISSN
- 1747-0277
- eISSN
- 1747-0285
- Publisher
- Wiley
- Number of pages
- 10
- Language
- English
- Date published
- 06/01/2007
- Academic Unit
- Biochemistry and Molecular Biology; Medicine Administration
- Record Identifier
- 9984627214802771
Metrics
14 Record Views