Novel synthetic molecules targeting the bacterial RNA polymerase assembly

• Published in: Journal of antimicrobial chemotherapy Vol. 57; no. 2; pp. 245 - 251
• Main Authors: André, Estelle, Bastide, Lionel, Michaux-Charachon, Sylvie, Gouby, Anne, Villain-Guillot, Philippe, Latouche, Jaqueline, Bouchet, Aurélie, Gualtiéri, Maxime, Leonetti, Jean-Paul
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2006; Oxford Publishing Limited (England)
• Subjects: Anti-Bacterial Agents - pharmacology; anti-infective agents; antibacterial drug screening; antibacterials; antibiotic resistance; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bacillus anthracis - drug effects; Bacillus cereus - drug effects; Bacteria; Bacteria - drug effects; Bacteria - enzymology; Biological and medical sciences; DNA-Directed RNA Polymerases - drug effects; Drug Resistance, Bacterial; Enzyme-Linked Immunosorbent Assay; Gram-Negative Bacteria - drug effects; Gram-Positive Bacteria - drug effects; Immunoprecipitation; Medical sciences; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Staphylococcus epidermidis - drug effects; Streptococcus pneumoniae - drug effects; transcription; Transcription, Genetic - drug effects; Drug; Targeting; Transcription; Enzyme; Transferases; Medical screening; DNA-directed RNA polymerase; Infection; Resistance; Screening; Nucleotidyltransferases; Antibiotic; Target; Synthetic product; antibacterial drug screening; antibiotic resistance; Bacteriosis; anti-infective agents; antibacterials; Bacteria; Antiinfectious; Antibacterial agent
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dki426

Objectives: Despite extensive functional screening of the bacterial RNA polymerase (RNAP) over the past years, very few novel inhibitors have been reported. We have, therefore, decided to screen with a radically different, non-enzymic, protein–protein interaction assay. Our target is the highly conserved RNAP–σ interaction that is essential for transcription. Methods: Small molecule inhibitors of the RNAP–σ interaction were tested for their activity on transcription and on bacteria. Results: These compounds have antibacterial activity against Gram-positive bacteria including multiresistant clinical isolates. Conclusions: This is, to our knowledge, the first example of a small molecule inhibitor of this interaction.