Antimicrobials targeted to the replication-specific DNA polymerases of Gram-positive bacteria: Target potential of dnaE

Infectious Disorders - Drug Targets

Volumn 12, Issue 5, 2012, Pages 327-331

  Barnes, Marjorie H ^a   Butler, Michelle M ^a   Wright, George E ^b   Brown, Neal C ^b  

^a MICROBIOTIX INC   (United States)

^b GLSYNTHESIS INC   (United States)

Author keywords

A form DNA; Antibacterials; B form DNA; DNA replication; DnaE; Pol IIIC

Indexed keywords

[3 (4 HYDROXYBUTYL) 6 (3 ETHYL 4 METHYLANILINO)URACIL]; [N(2) (3,4 DICHLOROBENZYL) 7 (5 METHOXY PENTYL)GUANINE]; [N(2) (3,4 DICHLOROBENZYL) 9 (3 CARBOXYPROPYL)GUANINE]; ANTIINFECTIVE AGENT; DEOXYGUANOSINE TRIPHOSPHATE; DNA POLYMERASE; UNCLASSIFIED DRUG;

ARTICLE; BACILLUS SUBTILIS; BACTERIAL STRAIN; BASE PAIRING; CHEMICAL STRUCTURE; DNA REPLICATION; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG TARGETING; ENZYME INHIBITION; GENE EXPRESSION; GRAM POSITIVE BACTERIUM; IC 50; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; POINT MUTATION;

ANTI-BACTERIAL AGENTS; BACILLUS SUBTILIS; DNA POLYMERASE III; DNA REPLICATION; DNA, BACTERIAL; DRUG DESIGN; GRAM-POSITIVE BACTERIA; GUANINE; MOLECULAR TARGETED THERAPY;

EID: 84872244544     PISSN: 18715265     EISSN: 18755852     Source Type: Journal    
DOI: 10.2174/187152612804142279     Document Type: Article

References (28)

1. Dervyn. E.; Suski, C.; Daniel, R.; Bruand, C.; Chapuis, J; Errington, J.; Janniere, L.; Ehrlich, S.D. Two essential DNA polymerases at the bacterial replication fork. Science, 2001, 294, 1716-1719.
2. Inoue, R.; Kaito, C.; Tanabe, M.; Kamura, K.; Akimitsu, N.; Sekimizu, K. Genetic identification of two distinct DNA polymerases, DnaE and PolC, that are essential for chromosomal DNA replication in Staphylococcus aureus. Mol. Genet. Genomics, 2001, 266, 564-571.
3. Wright, G.E.; Brown, N.C. DNA Polymerase III-A New Target for Antibiotic Development. Curr. Op. Anti-infec. Invest. Drugs, 1999, 1, 45-48.
4. Zhi, C.; Long, Z.-Y.; Manikowski, A.; Comstock, J.; Xu, W.-C.; Brown, N.C.; Tarantino, P.M., Jr.; Holm, K.A.; Dix, E.J.; Wright, G.E.; Barnes, M.H.; Butler, M.M.; Foster, K.A.; LaMarr, W.A.; Bachand, B.; Bethell, R.; Cadilhac, C.; Charron, S.; Lamothe, S.; Motorina, I.; Storer, R. Hybrid Antibacterials. DNA polymerase: topoisomerase inhibitors. J. Med. Chem., 2006, 49, 1455-1465.
5. Butler, M.M.; LaMarr, W.; Foster, K.A.; Barnes, M.H.; Skow, D.J.; Lyden, P.T.; Zhi, C.; Brown, N.C.; Wright, G.E.; Bowlin, T.L. Antibacterial Activity and Mechanism of Action of a Novel Anilinouracil: Fluoroquinolone Hybrid Compound. Antimicrob. Agents Chemother. 2007, 51, 119-127.
6. Torti, A.; Lossani, A.; Savi, L.; Focher, F.; Wright, G.E.; Brown, N.C.; Xu, W.-C. Clostridium difficile DNA Polymerase IIIC: Basis for Activity of Antibacterial Compounds. Curr. Enz. Inhib., 2011, 7, 147-153.
7. Dvoskin, S.; Xu, W.-C.; Brown, N. C; Yanachkov, I.B.; Yanachkova, M.; Wright, G.E. A Novel Agent Effective against Clostridium difficile Infection. Antimicrob. Agents Chemother., 2012, 56, 1624-1626.
8. Wright, G.E.; Brown, N.C.; Xu, W.-C.; Long, Z.-Y.; Zhi, C.; Gambino, J.J.; Barnes, M.H.; Butler, M.M. Active site directed inhibitors of replication-specific bacterial DNA polymerases. Bioorg. & Med. Chem. Lett., 2005, 15, 729-732.
9. 2-Substituted-3-deazaguanines. Synthesis, DNA polymerase III inhibition and antibacterial activity. Bioorg. Med. Chem. Lett., 2011, 21, 4197-4202.
10. Zhi, C.; Long, Z.-Y.; Gambino, J.; Xu, W.-C.; Brown, N.C.; Barnes, M.; Butler, M.; LaMarr, W.; Wright, G.E. Synthesis of substituted 6-anilinouracils and their inhibition of DNA polymerase IIIC and Gram-positive bacterial growth. J. Med Chem., 2003, 46, 2731-2739.
11. Barnes, M.H.; Hammond, R.A.; Kennedy, C.C.; Mack, S.L.; Brown, N.C. Localization of the exonuclease and polymerase domains of DNA polymerase III. Gene, 1992, 111, 43-49.
12. Gass, K.B.; Cozzarelli, N.R. Further genetic and enzymological characterization of the three Bacillus subtilis deoxyribonucleic acid polymerases. J. Biol. Chem., 1973, 248, 7688-7700.
13. Barnes, M.H.; Hammond, R.A.; Foster, K.A.; Mitchener, J.A.; Brown, N.C. The Cloned polC Gene of B. subtilis: Characterization of the azp12 Mutation and Controlled in vitro Synthesis of Active DNA Polymerase III. Gene, 1989, 85, 177-186.
14. Tarantino, P.; Zhi, C.; Wright, G.E.; Brown, N.C. Inhibitors of DNA Polymerase III as novel Antimicrobial Agents against Grampositive Eubacteria. Antimicrob. Agents Chemother., 1999, 43, 1982-1987.
15. Tarantino, P.; Zhi, C.; Gambino, J.; Wright, G.E.; Brown, N.C. 6-Anilinouracil-based Inhibitors of Bacillus subtilis DNA Polymerase III: Antipolymerase and Antimicrobial Structure-Activity Relationships based on Substitution at Uracil N3. J. Med. Chem., 1999, 42, 2035-2040.
16. Barnes, M.H.; Miller, S.D.; Brown, N.C. DNA Polymerases of low-GC Gram-Positive Eubacteria: Identification of the Replication-specific Enzyme Encoded by dnaE. J. Bacteriol., 2002, 184, 3834-3838.
17. Hammond, R.A.; Barnes, M.H.; Mack, S.L.; Mitchener, J.A.; Brown, N.C. Bacillus subtilis DNA Polymerase III: Complete Sequence, Overexpression, and Characterization of the polC Gene. Gene, 1991, 98, 29-36.
18. Wright, G.E.; Brown, N.C. Inhibition of Bacillus subtilis DNA Polymerase III by Arylhydrazinopyrimidines: Novel Properties of 2-Thiouracil Derivatives. Biochim. Biophys. Acta., 1976, 432, 37-48.
19. Brown, N.; Wisseman, C.; Matsushita, T. Inhibition of Bacterial DNA Replication by 6-(p-Hydroxyphenylazo)-uracil: Conditions for Inhibitory Activity in Toluene-treated Bacillus subtilis. Nature, 1972, 237, 72-74.
20. Brown, N.C.; Handschumacher, R.E. Inhibition of the Synthesis of Deoxyribonucleic Acid in Bacteria by 6-(p-Hydroxyphenylazo)-2,4-dihydroxypyrimidine. I. Metabolic studies in Streptococcus fecalis. J. Biol. Chem., 1966, 241, 3083-3089
21. Brown, N.C. p-Hydroxyphenylazouracil: A Selective Inhibitor of Host DNA Replication in Phage-infected Bacillus subtilis. Proc. Natl. Acad. Sci. USA, 1970, 67, l454-1461
22. Zhi, C.; Long, Z.-Y.; Manikowski, A.; Brown, N. C; Tarantino, P.M., Jr.; Holm, K.; Dix, E.J.; Wright, G.E.; Foster, K.A.; Butler, M.M.; LaMarr, W.A.; Skow, D.J.; Motorina, I.; Lamothe, S.; Storer, R. Synthesis and Antibacterial Activity of 3-Substituted-6-(3-ethyl-4-methylanilino)uracils. J. Med. Chem., 2005, 48, 7063-7074.
23. Clements, J.E.; D'Ambrosio, J.; Brown, N.C. Inhibition of Bacillus subtilis DNA Polymerase III by arylhydrazinopyrimidines: demonstration of a drug-induced DNA:enzyme complex J. Biol Chem., 1975, 250, 522-526.
24. Brown, N.C.; Wright, G.E. Mechanisms of inhibition of DNA Polymerases by 2'-Deoxyribonucleoside 5'-Triphosphate Analogs. Meth. Enzymology, 1995, 262, 202-217.
25. nd ed.; W. H. Freeman & Co. New York, 1991.
26. Sanders, G.M.; Dallmann, H.G.; McHenry, C.S. Reconstitution of the B. subtilis replisome with 13 proteins including two distinct replicases. Molec. Cell, 2010, 37, 273-281.
27. Ogawa, T.; Okazaki, T. Discontinuous DNA replication. Annu. Rev. Biochem.,1980, 49, 421-457.
28. Conn, G.L.; Brown, T.; Leonard, G.A. The crystal structure of the RNA/DNA hybrid r(GAAGAGAAGC)·d(GCTTCTCTTC) shows significant differences to that found in solution. Nucl. Acids Res., 1999, 27, 555-561.