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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:
; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1404962
Resource Type:
Journal Article
Resource Relation:
Journal Name: RNA Biology; Journal Volume: 13; Journal Issue: 10
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Howe, John A., Xiao, Li, Fischmann, Thierry O., Wang, Hao, Tang, Haifeng, Villafania, Artjohn, Zhang, Rumin, Barbieri, Christopher M., and Roemer, Terry. Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch. United States: N. p., 2016. Web. doi:10.1080/15476286.2016.1216304.
Howe, John A., Xiao, Li, Fischmann, Thierry O., Wang, Hao, Tang, Haifeng, Villafania, Artjohn, Zhang, Rumin, Barbieri, Christopher M., & Roemer, Terry. Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch. United States. doi:10.1080/15476286.2016.1216304.
Howe, John A., Xiao, Li, Fischmann, Thierry O., Wang, Hao, Tang, Haifeng, Villafania, Artjohn, Zhang, Rumin, Barbieri, Christopher M., and Roemer, Terry. 2016. "Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch". United States. doi:10.1080/15476286.2016.1216304.
@article{osti_1404962,
title = {Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch},
author = {Howe, John A. and Xiao, Li and Fischmann, Thierry O. and Wang, Hao and Tang, Haifeng and Villafania, Artjohn and Zhang, Rumin and Barbieri, Christopher M. and Roemer, Terry},
abstractNote = {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.},
doi = {10.1080/15476286.2016.1216304},
journal = {RNA Biology},
number = 10,
volume = 13,
place = {United States},
year = 2016,
month = 8
}
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