Department of Pharmacology and Molecular Toxicology
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
Medical Molecular Biology | Pharmacology | Toxicology
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.
Antimicrob Agents Chemother. 1999 Aug;43(8):1982-7.
Antimicrobial agents and chemotherapy
Tarantino, Paul M. Jr.; Zhi, Chengxin; Wright, George E.; and Brown, Neal C., "Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria" (1999). Open Access Articles. 183.