A new class of small molecule RNA polymerase inhibitors with activity against Rifampicin-resistant Staphylococcus aureus 1

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.

The structure–activity relationships around a Staphylococcus aureus RNA polymerase inhibitor in terms of inhibitory and antibacterial activities are presented. The antibacterial activity of selected members of this class of compounds, including some nanomolar inhibitors of the polymerase, is characterized. Several features of this class of compounds as antibacterials are highlighted.Figure optionsDownload as PowerPoint slide