title: Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch.
abstract: 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, ribocil 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. Herein, we expand our analysis of ribocil; including mode of binding in the FMN binding pocket of the riboswitch, mechanisms of resistance and structure-activity relationship guided efforts to generate more potent analogs.
authors.affiliation: a Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Howe
authors.affiliation: a Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.affiliation: a Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Thierry O
authors.initials: TO
authors.lastname: Fischmann
authors.affiliation: a Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: a Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Tang
authors.affiliation: a Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Artjohn
authors.initials: A
authors.lastname: Villafania
authors.affiliation: a Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Rumin
authors.initials: R
authors.lastname: Zhang
authors.affiliation: a Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Barbieri
authors.affiliation: a Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
keywords: Antibiotics; FMN riboswitch; RNA regulatory element; riboflavin