ABSTRACT
The RNA polymerase holoenzyme is a proven target for antibacterial agents. A high-throughput screening program based on this enzyme from Staphylococcus aureus had previously identified a 2-ureidothiophene-3-carboxylate as a low micromolar inhibitor. An investigation of the relationships between the structures of this class of compounds and their inhibitory- and antibacterial activities is described here, leading to a set of potent RNA polymerase inhibitors with antibacterial activity. Characterization of this bioactivity, including studies of the mechanism of action, is provided, highlighting the power of the reverse chemical genetics approach in providing tools to inhibit the bacterial RNA polymerase.
Subject(s)
Anti-Bacterial Agents/classification , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , Drug Resistance, Bacterial , Rifampin/pharmacology , Staphylococcus aureus/drug effects , Thiophenes/chemistry , Thiophenes/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA-Directed RNA Polymerases/metabolism , Molecular Structure , Molecular Weight , Structure-Activity RelationshipABSTRACT
The preparation and biological evaluation of 5-substituted-6-hydroxy-2-(anilino)pyrimidinones as a new class of DNA polymerase IIIC inhibitors, required for the replication of chromosomal DNA in Gram-positive bacteria, are described. These new dGTP competitive inhibitors displayed good levels of in vitro inhibition and antibacterial activity against Staphylococcus aureus. A new class of dATP competitive inhibitors, 6-substituted-2-amino-5-alkyl-pyrimidin-4-ones, whose antibacterial activity was unaffected by serum, were identified.