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Antimicrobial Agents and Chemotherapy, March 2005, p. 987-995, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.987-995.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Biological Characterization of Novel Inhibitors of the Gram-Positive DNA Polymerase IIIC Enzyme

Alexander Kuhl,1 Niels Svenstrup,1 Christoph Ladel,1,{dagger} Michael Otteneder,1,{ddagger} Annegret Binas,1 Guido Schiffer,1 Michael Brands,1 Thomas Lampe,1 Karl Ziegelbauer,1 Helga Rübsamen-Waigmann,1 Dieter Haebich,1 and Kerstin Ehlert1*

Bayer HealthCare AG, Pharma Research EU, Wuppertal, Germany1

Received 31 May 2004/ Returned for modification 11 July 2004/ Accepted 18 October 2004

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.

* Corresponding author. Mailing address: Bayer HealthCare AG, Pharma Research EU Antiinfectives I, Building 405, Aprather Weg 18a, D-42096 Wuppertal, Germany. Phone: (202) 368457. Fax: (202) 364116. E-mail: kerstin.ehlert{at}bayerhealthcare.com.

{dagger} Present address: RBM Serono, 10010 Colleretto Giacosa (To), Italy.

{ddagger} Present address: F. Hoffmann-La Roche Ltd., PRBN-S, CH-4070 Basel, Switzerland.

Antimicrobial Agents and Chemotherapy, March 2005, p. 987-995, Vol. 49, No. 3
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.3.987-995.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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