Antibacterial activity and mechanism of action of a novel anilinouracil-fluoroquinolone hybrid compound.

The anilinouracils (AUs) such as 6-(3-ethyl-4-methylanilino)uracil (EMAU) are a novel class of gram-positive, selective, bactericidal antibacterials which inhibit pol IIIC, the gram-positive-specific replicative DNA polymerase. We have linked various fluoroquinolones (FQs) to the N-3 position of EMAU to generate a variety of AU-FQ "hybrids" offering the potential for targeting two distinct steps in DNA replication. In this study, the properties of a hybrid, "251D," were compared with those of representative AUs and FQs in a variety of in vitro assays, including pol IIIC and topoisomerase/gyrase enzyme assays, antibacterial, bactericidal, and mammalian cytotoxicity assays.

Low frequencies of resistance among Staphylococcus and Enterococcus species to the bactericidal DNA polymerase inhibitor N(3)-hydroxybutyl 6-(3'-ethyl-4'-methylanilino) uracil.

The 6-anilinouracils (AUs) constitute a new class of bactericidal antibiotics selective against gram-positive (Gr(+)) organisms. The AU family of compounds specifically inhibits a novel target, replicative DNA polymerase Pol IIIC. Like other antibiotics, AUs can be expected to engender the development of resistant bacteria.