{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T05:51:00Z","timestamp":1760853060232},"reference-count":31,"publisher":"American Society for Microbiology","issue":"3","license":[{"start":{"date-parts":[[2005,3,1]],"date-time":"2005-03-01T00:00:00Z","timestamp":1109635200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2005,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>Novel N-3-alkylated 6-anilinouracils have been identified as potent and selective inhibitors of bacterial DNA polymerase IIIC, the enzyme essential for the replication of chromosomal DNA in gram-positive bacteria. A nonradioactive assay measuring the enzymatic activity of the DNA polymerase IIIC in gram-positive bacteria has been assembled. The 6-anilinouracils described inhibited the polymerase IIIC enzyme at concentrations in the nanomolar range in this assay and displayed good in vitro activity (according to their MICs) against staphylococci, streptococci, and enterococci. The MICs of the most potent derivatives were about 4 \u03bcg\/ml for this panel of bacteria. The 50% effective dose of the best compound (6-[(3-ethyl-4-methylphenyl)amino]-3-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]methyl}uracil) was 10 mg\/kg of body weight after intravenous application in a staphylococcal sepsis model in mice, from which in vivo pharmacokinetic data were also acquired.<\/jats:p>","DOI":"10.1128\/aac.49.3.987-995.2005","type":"journal-article","created":{"date-parts":[[2005,2,23]],"date-time":"2005-02-23T22:51:53Z","timestamp":1109199113000},"page":"987-995","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Biological Characterization of Novel Inhibitors of the Gram-Positive DNA Polymerase IIIC Enzyme"],"prefix":"10.1128","volume":"49","author":[{"given":"Alexander","family":"Kuhl","sequence":"first","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niels","family":"Svenstrup","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Ladel","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Otteneder","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annegret","family":"Binas","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guido","family":"Schiffer","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Brands","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Lampe","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl","family":"Ziegelbauer","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helga","family":"Ru\u0308bsamen-Waigmann","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dieter","family":"Haebich","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerstin","family":"Ehlert","sequence":"additional","affiliation":[{"name":"Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1016\/S0960-894X(01)00407-3","volume":"11","year":"2001","unstructured":"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.","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm020483c"},{"key":"e_1_3_2_4_2","unstructured":"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."},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(92)90601-K"},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1080\/00498250410001685719","volume":"34","year":"2004","unstructured":"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. Xenobiotica34:571-579.","journal-title":"Xenobiotica"},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/BF01062336","volume":"10","year":"1982","unstructured":"Boxenbaum, H. 1982. Interspecies scaling, allometry, physiological time and the ground plan of pharmacokinetics. J. Pharmacokinet. Biopharm.10:201-227.","journal-title":"J. Pharmacokinet. Biopharm."},{"key":"e_1_3_2_8_2","unstructured":"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."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.46.12.3770-3775.2002"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.8.2217-2221.2000"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1066351"},{"key":"e_1_3_2_12_2","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1073\/pnas.70.1.103","volume":"70","year":"1973","unstructured":"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. USA70:103-107.","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004380100564"},{"key":"e_1_3_2_14_2","doi-asserted-by":"crossref","first-page":"26136","DOI":"10.1074\/jbc.M002566200","volume":"275","year":"2000","unstructured":"Klemperer, N., D. Zhang, M. Skangalis, and M. O'Donnell. 2000. Cross-utilization of the \u03b2 sliding clamp by replicative polymerases of evolutionary divergent organisms. J. Biol. Chem.275:26136-26143.","journal-title":"J. Biol. Chem."},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)33742-0"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(85)90211-8"},{"key":"e_1_3_2_17_2","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0003-2697(87)90158-8","volume":"167","year":"1987","unstructured":"Nyren, P. 1987. Enzymatic method for continuous monitoring of DNA polymerase activity. Anal. Biochem.167:235-238.","journal-title":"Anal. Biochem."},{"key":"e_1_3_2_18_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0378-1119(95)00377-I","volume":"165","year":"1995","unstructured":"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. Gene165:51-56.","journal-title":"Gene"},{"key":"e_1_3_2_19_2","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/BF00260660","volume":"226","year":"1991","unstructured":"Sanjanwala, B., and T. Ganesan. 1991. Genetic structure and domains of DNA polymerase III of B. subtilis. Mol. Gen. Genet.226:467-472.","journal-title":"Mol. Gen. Genet."},{"key":"e_1_3_2_20_2","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1002\/1520-6017(200008)89:8<1008::AID-JPS5>3.0.CO;2-B","volume":"89","year":"2000","unstructured":"Schuhmacher, J., K. B\u00fchner, 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.","journal-title":"J. Pharm. Sci."},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/43.suppl_2.69"},{"key":"e_1_3_2_22_2","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1080\/00498250210158249","volume":"32","year":"2002","unstructured":"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. Xenobiotica32:907-924.","journal-title":"Xenobiotica"},{"key":"e_1_3_2_23_2","first-page":"1136","volume":"29","year":"2001","unstructured":"Slatter, J. G., D. J. Stalker, K. L. Feenstra, I. R. Welshman, J. B. Bruss, J. P. Sams, M. G. Johnson, P. E. Sanders, M. J. Hauer, P. E. Fagerness, R. P. Stryd, G. W. Peng, and E. M. Shobe. 2001. Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [14C]linezolid to healthy human subjects. Drug Metab. Dispos.29:1136-1145.","journal-title":"Drug Metab. Dispos."},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-139-9-2041"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm980693i"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.8.1982"},{"key":"e_1_3_2_27_2","first-page":"1247","volume":"330","year":"1994","unstructured":"Tomasz, A. 1994. Multiple-antibiotic-resistant pathogenic bacteria. N. Engl. J. Med.330:1247-1251.","journal-title":"N. Engl. J. Med."},{"key":"e_1_3_2_28_2","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1021\/jm00155a016","volume":"29","year":"1986","unstructured":"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.","journal-title":"J. Med. Chem."},{"key":"e_1_3_2_29_2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1021\/jm00175a007","volume":"23","year":"1980","unstructured":"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.","journal-title":"J. Med. Chem."},{"key":"e_1_3_2_30_2","first-page":"45","volume":"1","year":"1999","unstructured":"Wright, G. E., and N. C. Brown. 1999. DNA polymerase III: a new target for antibiotic developement. Curr. Opin. Anti-Infect. Investig. Drugs1:45-48.","journal-title":"Curr. Opin. Anti-Infect. Investig. Drugs"},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1006\/abio.2001.5591","volume":"304","year":"2002","unstructured":"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.","journal-title":"Anal. Biochem."},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm020591z"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.49.3.987-995.2005","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.49.3.987-995.2005","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T18:44:38Z","timestamp":1645469078000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.49.3.987-995.2005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,3]]},"references-count":31,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2005,3]]}},"alternative-id":["10.1128\/AAC.49.3.987-995.2005"],"URL":"https:\/\/doi.org\/10.1128\/aac.49.3.987-995.2005","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,3]]},"assertion":[{"value":"2004-05-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2004-10-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2005-03-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}