title: Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria.
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.
authors.affiliation: Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Tarantino
authors.forename: C
authors.initials: C
authors.lastname: Zhi
authors.forename: G E
authors.initials: GE
authors.lastname: Wright
authors.forename: N C
authors.initials: NC
authors.lastname: Brown
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects / Q000201:enzymology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002417:Cattle; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D013293:Enterococcus faecalis / Q000187:drug effects / Q000201:enzymology; D016984:Enterococcus faecium / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology*; D007700:Kinetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D014498:Uracil; D004258:DNA Polymerase III