Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria

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-p ositive bacterial pathogens, Favorable in vitro properties of N-3-alkyl der ivatives prompted the synthesis of derivatives in which the R group at N-3 was replaced with more-hydrophilic methoxyalkyl. and hydroxyalkyl groups. T hese hydroxyalkyl and methoxyalkyl derivatives displayed Ki values in the r ange from 0.4 to 2.8 mu M against relevant gram-positive bacterial DNA poly merase IIIs and antimicrobial activity with MICs in the range from 0.5 to 1 5 mu g/ml against a broad spectrum of gram-positive bacteria, including met hicillin-resistant staphylococci and vancomycin-resistant enterococci, Two of these hydrophilic derivatives displayed protective activity in a simple mouse model of lethal staphylococcal infection.