The objective of this research is to discover novel compounds with antibacterial properties that acts by inhibition of a bacterial-specific transcription termination factor. In bacteria, about half of the transcription termination events are mediated by a protein factor known as Rho. Transcription termination is important in regulation of gene expression and in formation of messenger RNA 3' termini. Rho is a relevant target for an anti-bacterial drug discovery program since it is an essential protein that is conserved across bacterial species but not present in eucaryotic cells. We plan to synthesize and evaluate 100,000-400,000 compounds for inhibition of the ATPase activity of Rho. Most will be designed to bind to RNA and RNA binding proteins. Compounds that are active in the ATPase assay will be evaluated in secondary assays including an in vitro assay for inhibition of Rho- dependent transcription termination. Compounds will also be tested for anti-bacterial activity in liquid media and for toxicity to eucaryotic cells. The anticipated outcome of this phase of research is a set of novel compounds ready for testing in animal models of bacterial infection.
New antimicrobial agents are desperately needed as bacteria become resistant to antibiotics presently in clinical use. By targeting transcription termination factor Rho with novel compounds from our combinatorial chemistry effort, we have the potential to discover a novel, broad spectrum antimicrobial with low toxicity to the host.
