A new class of small molecule RNA polymerase inhibitors with activity against Rifampicin-resistant Staphylococcus aureus1

Francis Arhin, Odette Bélanger, Stéphane Ciblat, Mohammed Dehbi, Daniel Delorme, Evelyne Dietrich, Dilip Dixit, Yanick Lafontaine, Dario Lehoux, Jing Liu, Geoffrey A. McKay, Greg Moeck, Ranga Reddy, Yannick Rose, Ramakrishnan Srikumar, Kelly S E Tanaka, Daniel M. Williams, Philippe Gros, Jerry Pelletier, Thomas R. ParrAdel Rafai Far

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41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5812-5832
Number of pages21
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number17
DOIs
Publication statusPublished - 1 Sep 2006
Externally publishedYes

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Keywords

  • 2-Ureidothiophene-3-carboxylates
  • Antibacterial agents
  • Reverse chemical genetics
  • RNA polymerase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Arhin, F., Bélanger, O., Ciblat, S., Dehbi, M., Delorme, D., Dietrich, E., Dixit, D., Lafontaine, Y., Lehoux, D., Liu, J., McKay, G. A., Moeck, G., Reddy, R., Rose, Y., Srikumar, R., Tanaka, K. S. E., Williams, D. M., Gros, P., Pelletier, J., ... Far, A. R. (2006). A new class of small molecule RNA polymerase inhibitors with activity against Rifampicin-resistant Staphylococcus aureus1 Bioorganic and Medicinal Chemistry, 14(17), 5812-5832. https://doi.org/10.1016/j.bmc.2006.05.035