Biological characterization of novel inhibitors of the gram-positive DNA polymerase IIIC enzyme

Antimicrobial Agents and Chemotherapy

Volumn 49, Issue 3, 2005, Pages 987-995

  Kuhl, Alexander ^a   Svenstrup, Niels ^a   Ladel, Christoph ^a,b   Otteneder, Michael ^a,c   Binas, Annegret ^a   Schiffer, Guido ^a   Brands, Michael ^a   Lampe, Thomas ^a   Ziegelbauer, Karl ^a   Rübsamen Waigmann, Helga ^a   Haebich, Dieter ^a   Ehlert, Kerstin ^a  

^a BAYER PHARMA AG   (Germany)

^b Merck Serono SpA   (Italy)

^c F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

6 [(3 ETHYL 4 METHYLPHENYL)AMINO] 3 [[1 (ISOXAZOL 5 YLCARBONYL)PIPERIDIN 4 YL]METHYL]URACIL; DNA DIRECTED DNA POLYMERASE GAMMA; DNA DIRECTED DNA POLYMERASE GAMMA C; DNA POLYMERASE; ENZYME INHIBITOR; UNCLASSIFIED DRUG; URACIL DERIVATIVE;

ALKYLATION; ANTIBIOTIC THERAPY; ARTICLE; BACTERIUM IDENTIFICATION; DERIVATIZATION; DRUG EFFECT; ENZYME ACTIVITY; ENZYME INHIBITION; GRAM POSITIVE BACTERIUM; HOSPITAL INFECTION; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONTENT; PROTEIN DOMAIN; PROTEIN FAMILY; SEPSIS; STRUCTURAL GENE;

ANIMALS; ANTI-BACTERIAL AGENTS; DNA; DNA POLYMERASE III; DOGS; ENZYME INHIBITORS; FEMALE; GRAM-POSITIVE BACTERIA; MALE; MICE; MICROBIAL SENSITIVITY TESTS; RATS; RATS, WISTAR; STAPHYLOCOCCUS AUREUS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 20044372000     PISSN: 00664804     EISSN: None     Source Type: Journal    
DOI: 10.1128/AAC.49.3.987-995.2005     Document Type: Article

References (31)

1. Ali, A., S. D. Aster, D. W. Graham, G. F. Patel, G. E. Taylor, R. L. Tolman, R. E. Painter, L. L. Silver, K. Young, K. Ellsworth, W. Geissler, and G. S. Harris. 2001. Design and synthesis of novel antimicrobial agents with inhibitory activity against DNA polymerase III. Bioorg. Med. Chem. Lett. 11:2185-2188.
2. Ali, A., G. E. Taylor, K. Ellsworth, G. Harris, R. Painter, L. L. Silver, and K. Young. 2003. Novel pyrazolo[3,4-d]pyrimidine-based inhibitors of Staphylococcus aureus DNA polymerase III: design, synthesis, and biological evaluation. J. Med. Chem. 46:1824-1830.
3. Ali, A., G. E. Taylor and D. W. Graham. April 2001. Gram-positive selective antibacterial compounds, compositions containing such compounds and methods of treatment. Patent WO 01/29010.
4. Barnes, M. H., R. A. Hammond, C. C. Kennedy, S. L. Mack, and N. C. Brown. 1992. Localization of the exonuclease and polymerase domains of Bacillus subtilis DNA polymerase III. Gene 111:43-49.
5. Bhamidipati, R. K., P. V. Dravid, R. Mullangi, and N. R. Srinivas. 2004. Prediction of clinical pharmacokinetic parameters of linezolid using animal data by allometric scaling: applicability for the development of novel oxazolidinones. Xenobiotica 34:571-579.
6. Boxenbaum, H. 1982. Interspecies scaling, allometry, physiological time and the ground plan of pharmacokinetics. J. Pharmacokinet. Biopharm. 10:201-227.
7. Brown, N. C., and G. E. Wright. March 1996. Antibiotic compounds and methods to treat gram-positive bacterial and mycoplasmal infections. Patent WO 96/06614.
8. Butler, M. M., D. J. Skow, R. O. Stephenson, P. T. Lyden, W. A. LaMarr, and K. A. Foster. 2002. Low frequencies of resistance among Staphylococcus and Enterococcus species to the bactericidal DNA polymerase inhibitor N(3)-hydroxybutyl 6-(3′-ethyl-4′-methylanilino) uracil. Antimicrob. Agents Chemother. 46:3770-3775.
9. Daly, J. S., T. J. Giehl, N. C. Brown, C. Zhi, G. E. Wright, and R. T. Ellison. 2000. In vitro antimicrobial activities of novel anilinouracils which selectively inhibit DNA polymerase III of gram-positive bacteria. Antimicrob. Agents Chemother. 44:2217-2221.
10. Dervyn, E., C. Suski, R. Daniel, C. Bruand, J. Chapuis, J. Errington, L. Janniere, and S. D. Ehrlich. 2001. Two essential DNA polymerases at the replication fork. Science 294:1716-1719.
11. Gass, K. B., R. L. Low, and N. R. Cozzarelli. 1973. Inhibition of a DNA polymerase from Bacillus subtilis by hydroxyphenylazopyrimidines. Proc. Natl. Acad. Sci. USA 70:103-107.
12. Inoue, R., C. Kaito, M. Tanabe, K. Kamura, N. Akimitsu, and K. Sekimizu. 2001. Genetic identification of two distinct DNA polymerases, DnaE and PolC, that are essential for chromosomal DNA replication in Staphylococcus aureus. Mol. Genet. Genomics 266:564-571.
13. Klemperer, N., D. Zhang, M. Skangalis, and M. O'Donnell. 2000. Cross-utilization of the β sliding clamp by replicative polymerases of evolutionary divergent organisms. J. Biol. Chem. 275:26136-26143.
14. Low, R. L., S. A. Rashbaum, and N. R. Cozzarelli. 1976. Purification and characterization of DNA polymerase III from Bacillus subtilis. J. Biol. Chem. 251:1311-1325.
15. Nyren, P., and A. Lundin. 1985. Enzymatic method for continuous monitoring of inorganic pyrophosphate synthesis. Anal. Biochem. 151:504-509.
16. Nyren, P. 1987. Enzymatic method for continuous monitoring of DNA polymerase activity. Anal. Biochem. 167:235-238.
17. Pacitti, D. F., M. H. Barnes, D. H. Li, and N. C. Brown. 1995. Characterization and overexpression of the gene encoding Staphylococcus aureus DNA polymerase III. Gene 165:51-56.
18. Sanjanwala, B., and T. Ganesan. 1991. Genetic structure and domains of DNA polymerase III of B. subtilis. Mol. Gen. Genet. 226:467-472.
19. Schuhmacher, J., K. Bühner, and A. Witt-Laido. 2000. Determination of the free fraction and relative free fraction of drugs strongly bound to plasma proteins. J. Pharm. Sci. 89:1008-1021.
20. Siefert, H. M., A. Domdey-Bette, K. Henninger, F. Hucke, C. Kohlsdorfer, and H. H. Stass. 1999. Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: a comparison in humans and other mammalian species. J. Antimicrob. Chemother. 43:69-76.
21. Slatter, J. G., L. A. Adams, E. C. Bush, K. Chiba, P. T. Daley-Yates, K. L. Feenstra, S. Koike, N. Ozawa, G. W. Peng, J. P. Sams, M. R. Schuette, and S. Yamazaki. 2002. Pharmacokinetics, toxicokinetics, distribution, metabolism and excretion of linezolid in mouse, rat and dog. Xenobiotica 32:907-924.
22. 14C]linezolid to healthy human subjects. Drug Metab. Dispos. 29:1136-1145.
23. Stulke, J., R. Hanschke, and M. Hecker. 1993. Temporal activation of beta-glucanase synthesis in Bacillus subtilis is mediated by the GTP pool. J. Gen. Microbiol. 139:2041-2045.
24. Tarantino, P. M., C. Zhi, J. J. Gambino, G. E. Wright, and N. C. Brown. 1999. 6-Anilinouracil-based inhibitors of B. subtilis DNA polymerase III. Antipolymerase and antimicrobial structure-activity relationships based on substitution at uracil N3. J. Med. Chem. 42:2035-2040.
25. Tarantino, P. M., C. Zhi, G. E. Wright, and N. C. Brown. 1999. Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria. Antimicrob. Agents Chemother. 43:1982-1987.
26. Tomasz, A. 1994. Multiple-antibiotic-resistant pathogenic bacteria. N. Engl. J. Med. 330:1247-1251.
27. Trantolo, D. J., G. E. Wright, and N. C. Brown. 1986. Inhibitors of B. subtilis DNA polymerase III. Influence of modifications in the pyrimidine ring of anilino- and (benzylamino)pyrimidines. J. Med. Chem. 29:676-681.
28. Wright, G. E., and N. C. Brown. 1980. Inhibitors of Bacillus subtilis DNA polymerase III. 6-Anilinouracils and 6-(alkylamino)uracils. J. Med. Chem. 23:34-38.
29. Wright, G. E., and N. C. Brown. 1999. DNA polymerase III: a new target for antibiotic developement. Curr. Opin. Anti-Infect. Investig. Drugs 1:45-48.
30. Yang, F., I. B. Dicker, M. G. Kurilla, and D. L. Pompliano. 2002. PolC-type polymerase III of Streptococcus pyogenes and its use in screening for chemical inhibitors. Anal. Biochem. 304:110-116.
31. Zhi, C., Z. Y. Long, J. Gambino, W. C. Xu, N. C. Brown, M. Barnes, M. M. Butler, W. LaMarr, and G. E. Wright. 2003. Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and gram-positive bacterial growth. J. Med. Chem. 46:2731-2739.