Discovery of the first small-molecule CsrA–RNA interaction inhibitors using biophysical screening technologies. (June 2016)

• Record Type: Journal Article
• Authors: Maurer, Christine K; Fruth, Martina; Empting, Martin; Avrutina, Olga; Hoßmann, Jörn; Nadmid, Suvd; Gorges, Jan; Herrmann, Jennifer; Kazmaier, Uli; Dersch, Petra; Müller, Rolf; Hartmann, Rolf W
• Is Part Of: Future medicinal chemistry. Volume 8:Number 9(2016)
• Page Start: 931
• Page End: 947
• Publication Date: 2016-06
• Subjects: anti-virulence strategy -- CsrA/RsmA protein family -- fluorescence polarization -- library screening -- protein–nucleic acid interaction -- surface plasmon resonance spectroscopy; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2016-0033
• Languages: English
• ISSNs: 1756-8919

Abstract

Aim: CsrA is a global post-transcriptional regulator protein affecting mRNA translation and/or stability. Widespread among bacteria, it is essential for their full virulence and thus represents a promising anti-infective drug target. Therefore, we aimed at the discovery of CsrA–RNA interaction inhibitors.Results & methodology: We followed two strategies: a screening of small molecules (A) and an RNA ligand-based approach (B). Using surface plasmon resonance-based binding and fluorescence polarization-based competition assays, (A) yielded seven small-molecule inhibitors, among them MM14 (IC50 of 4 µM). (B) resulted in RNA-based inhibitor GGARNA (IC50 of 113 µM).Conclusion: The first small-molecule inhibitors of the CsrA–RNA interaction were discovered exhibiting micromolar affinities. These hits represent tools to investigate the effects of CsrA–RNA interaction inhibition on bacterial virulence.