In vitro antimicrobial activities of novel anilinouracils which selectively inhibit DNA polymerase III of gram-positive bacteria.
The 6-anilinouracils are novel dGTP analogs that selectively inhibit the replication-specific DNA polymerase III of gram-positive eubacteria. Two specific derivatives, IMAU (6-[3'-iodo-4'-methylanilino]uracil) and EMAU (6-[3'-ethyl-4'-methylanilino]uracil), were substituted with either a hydroxybutyl (HB) or a methoxybutyl (MB) group at their N3 positions to produce four agents: HB-EMAU, MB-EMAU, HB-IMAU, and MB-IMAU. These four new agents inhibited Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Enterococcus faecium. Time-kill assays and broth dilution testing confirmed bactericidal activity. These anilinouracil derivatives represent a novel class of antimicrobials with promising activities against gram-positive bacteria that are resistant to currently available agents, validating replication-specific DNA polymerase III as a new target for antimicrobial development.
Daly
J S
JS
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester 01655, USA. dalyj01@ummhc.org
Giehl
T J
TJ
Brown
N C
NC
Zhi
C
C
Wright
G E
GE
Ellison
R T
RT
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D016983:Enterococcus / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology*
C413944:6-(3'-ethyl-4'-methylanilino)uracil; C413943:6-(3'-iodo-4'-methylanilino)uracil; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D014498:Uracil; D004258:DNA Polymerase III