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-sigma interaction that is essential for transcription. METHODS: Small molecule inhibitors of the RNAP-sigma 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.
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-sigma interaction that is essential for transcription. METHODS: Small molecule inhibitors of the RNAP-sigma 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.
Authors: Andrew Robinson; Anthony J Brzoska; Kylie M Turner; Ryan Withers; Elizabeth J Harry; Peter J Lewis; Nicholas E Dixon Journal: Microbiol Mol Biol Rev Date: 2010-06 Impact factor: 11.056
Authors: Deborah Mai; Jennifer Jones; John W Rodgers; John L Hartman; Olaf Kutsch; Adrie J C Steyn Journal: Assay Drug Dev Technol Date: 2011-01-31 Impact factor: 1.738
Authors: S A El-Mowafi; E Sineva; J N Alumasa; H Nicoloff; J W Tomsho; S E Ades; K C Keiler Journal: Antimicrob Agents Chemother Date: 2014-10-20 Impact factor: 5.191
Authors: Nathan T Scharf; Vadim Molodtsov; Arrin Kontos; Katsuhiko S Murakami; George A Garcia Journal: SLAS Discov Date: 2016-12-27 Impact factor: 3.341