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-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 Ki values in the range from 0.4 to 2.8 mM against relevant gram-positive bacterial DNA polymerase IIIs and antimicrobial activity with MICs in the range from 0.5 to 15 mg/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. The escalating incidence of infection with multiple-antibiot-ic-resistant forms of low G1C content gram-positive bacteria is a major and rapidly growing clinical problem (20). In an effort to address this problem, we have sought to identify a ne