ribocil and Escherichia-coli-Infections

Riboswitches are non-coding RNA structures located in messenger RNAs that bind endogenous ligands, such as a specific metabolite or ion, to regulate gene expression. As such, riboswitches serve as a novel, yet largely unexploited, class of emerging drug targets. Demonstrating this potential, however, has proven difficult and is restricted to structurally similar antimetabolites and semi-synthetic analogues of their cognate ligand, thus greatly restricting the chemical space and selectivity sought for such inhibitors. Here we report the discovery and characterization of ribocil, a highly selective chemical modulator of bacterial riboflavin riboswitches, which was identified in a phenotypic screen and acts as a structurally distinct synthetic mimic of the natural ligand, flavin mononucleotide, to repress riboswitch-mediated ribB gene expression and inhibit bacterial cell growth. Our findings indicate that non-coding RNA structural elements may be more broadly targeted by synthetic small molecules than previously expected.

Topics: Animals; Aptamers, Nucleotide; Bacteria; Base Sequence; Crystallography, X-Ray; Escherichia coli Infections; Escherichia coli Proteins; Female; Flavin Mononucleotide; Gene Expression Regulation, Bacterial; Heat-Shock Proteins; Intramolecular Transferases; Ligands; Mice; Mice, Inbred DBA; Models, Molecular; Molecular Sequence Data; Pyrimidines; Reproducibility of Results; Riboflavin; Riboswitch; RNA, Bacterial; Substrate Specificity