1. A new class of small molecule RNA polymerase inhibitors with activity against rifampicin-resistant Staphylococcus aureus.
- Author
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Arhin F, Bélanger O, Ciblat S, Dehbi M, Delorme D, Dietrich E, Dixit D, Lafontaine Y, Lehoux D, Liu J, McKay GA, Moeck G, Reddy R, Rose Y, Srikumar R, Tanaka KS, Williams DM, Gros P, Pelletier J, Parr TR Jr, and Far AR
- Subjects
- Anti-Bacterial Agents chemistry, Anti-Bacterial Agents pharmacology, DNA-Directed RNA Polymerases metabolism, Molecular Structure, Molecular Weight, Structure-Activity Relationship, 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
- 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.
- Published
- 2006
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