Biological Characterization of Novel Inhibitors of the Gram-Positive DNA Polymerase IIIC Enzyme
| Autor: | Dieter Haebich, Alexander Kuhl, Annegret Binas, Christoph Ladel, Karl Ziegelbauer, Michael Otteneder, Thomas Lampe, Helga Rübsamen-Waigmann, Niels Svenstrup, Michael Brands, Guido Schiffer, Kerstin Ehlert |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Staphylococcus aureus DNA polymerase Gram-positive bacteria Microbial Sensitivity Tests Gram-Positive Bacteria Mice Structure-Activity Relationship chemistry.chemical_compound Dogs Animals Pharmacology (medical) Enzyme Inhibitors Rats Wistar Mechanisms of Action: Physiological Effects Polymerase DNA Polymerase III Pharmacology chemistry.chemical_classification biology Uracil DNA biology.organism_classification Molecular biology In vitro Anti-Bacterial Agents Rats Infectious Diseases Enzyme chemistry Biochemistry biology.protein Female Bacteria |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 49:987-995 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.49.3.987-995.2005 |
| Popis: | 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 μg/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. |
| Databáze: | OpenAIRE |
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