| Autor: |
Lerner CG; Abbott Global Pharmaceutical Research and Development, Abbott Park, IL 60064-6098, USA., Hajduk PJ, Wagner R, Wagenaar FL, Woodall C, Gu YG, Searle XB, Florjancic AS, Zhang T, Clark RF, Cooper CS, Mack JC, Yu L, Cai M, Betz SF, Chovan LE, McCall JO, Black-Schaefer CL, Kakavas SJ, Schurdak ME, Comess KM, Walter KA, Edalji R, Dorwin SA, Smith RA, Hebert EJ, Harlan JE, Metzger RE, Merta PJ, Baranowski JL, Coen ML, Thornewell SJ, Shivakumar AG, Saiki AY, Soni N, Bui M, Balli DJ, Sanders WJ, Nilius AM, Holzman TF, Fesik SW, Beutel BA |
| Jazyk: |
angličtina |
| Zdroj: |
Chemical biology & drug design [Chem Biol Drug Des] 2007 Jun; Vol. 69 (6), pp. 395-404. |
| DOI: |
10.1111/j.1747-0285.2007.00521.x |
| Abstrakt: |
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 biphenyl acid lead series emerged from an NMR-based screen with the Haemophilus influenzae protein HI0065, 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 HI0065, 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 gene products that are not present in eukaryotic cells can identify novel antibacterial agents. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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