Bacterial riboswitches are non-coding RNA structural elements that direct gene expression in numerous metabolic pathways. The key regulatory roles of riboswitches, and the urgent need for new classes of antibiotics to treat multi-drug resistant bacteria, has led to efforts to develop small-molecules that mimic natural riboswitch ligands to inhibit metabolic pathways and bacterial growth. Recently, we reported the results of a phenotypic screen targeting the riboflavin biosynthesis pathway in the Gram-negative bacteria, Escherichia coli that led to the identification of ribocil, a small molecule inhibitor of the flavin mononucleotide (FMN) riboswitch controlling expression of this biosynthetic pathway. Although ribocil is structurally distinct from FMN, it functions as a potent and highly selective synthetic mimic of the natural ligand to repress riboswitch-mediated ribB gene expression and inhibit bacterial growth both in vitro and in vivo. In this presentation, we will show our computer modeling studies on small molecule binding interactions with E. coli FMN riboswitch, including homology modeling, docking and binding free energy calculations, and highlight key factors influencing binding potency of ribocil and its analogs. We will also provide detailed structural analysis on mechanisms of resistance of ribocil. Our structure-based drug design effort led to more potent analogs of the series. Structural and mechanistic insights into ribocil binding and resistance should offer new opportunities in the design and optimization of ligands targeting RNA structural elements.

Molecular drug design targeting a bacterial RNA structure: Atomic resolution mechanistic studies of highly selective unnatural ligand mimic of the E. coli FMN riboswitch

253rd National Meeting (2017)

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