UMMS Affiliation

Department of Pharmacology and Molecular Toxicology

Publication Date

8-3-1999

Document Type

Article

Subjects

Aniline Compounds; Animals; Anti-Bacterial Agents; Bacillus subtilis; Bacterial Proteins; Cattle; DNA Polymerase III; Enterococcus faecalis; Enterococcus faecium; Enzyme Inhibitors; Female; Gram-Positive Bacteria; Kinetics; Mice; Microbial Sensitivity Tests; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Uracil

Disciplines

Medical Molecular Biology | Pharmacology | Toxicology

Abstract

6-Anilinouracils are selective inhibitors of DNA polymerase III, the enzyme required for the replication of chromosomal DNA in gram-positive bacteria (N. C. Brown, L. W. Dudycz, and G. E. Wright, Drugs Exp. Clin. Res. 12:555-564, 1986). A new class of 6-anilinouracils based on N-3 alkyl substitution of the uracil ring was synthesized and analyzed for activity as inhibitors of the gram-positive bacterial DNA polymerase III and the growth of gram-positive bacterial pathogens. Favorable in vitro properties of N-3-alkyl derivatives prompted the synthesis of derivatives in which the R group at N-3 was replaced with more-hydrophilic methoxyalkyl and hydroxyalkyl groups. These hydroxyalkyl and methoxyalkyl derivatives displayed K(i) values in the range from 0.4 to 2.8 microM against relevant gram-positive bacterial DNA polymerase IIIs and antimicrobial activity with MICs in the range from 0.5 to 15 microg/ml against a broad spectrum of gram-positive bacteria, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. Two of these hydrophilic derivatives displayed protective activity in a simple mouse model of lethal staphylococcal infection.

Rights and Permissions

Citation: Antimicrob Agents Chemother. 1999 Aug;43(8):1982-7.

Related Resources

Link to article in PubMed

Journal/Book/Conference Title

Antimicrobial agents and chemotherapy

PubMed ID

10428923

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