title: Small molecule fluoride toxicity agonists.
abstract: Fluoride is a ubiquitous anion that inhibits a wide variety of metabolic processes. Here, we report the identification of a series of compounds that enhance fluoride toxicity in Escherichia coli and Streptococcus mutans. These molecules were isolated by using a high-throughput screen (HTS) for compounds that increase intracellular fluoride levels as determined via a fluoride riboswitch reporter fusion construct. A series of derivatives were synthesized to examine structure-activity relationships, leading to the identification of compounds with improved activity. Thus, we demonstrate that small molecule fluoride toxicity agonists can be identified by HTS from existing chemical libraries by exploiting a natural fluoride riboswitch. In addition, our findings suggest that some molecules might be further optimized to function as binary antibacterial agents when combined with fluoride.
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Nelson
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Plummer
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Blount
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Tyler D
authors.initials: TD
authors.lastname: Ames
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA. Electronic address: ronald.breaker@yale.edu.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Breaker
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D005459:Fluorides / Q000819:agonists / Q000737:chemistry* / Q000633:toxicity*; D057166:High-Throughput Screening Assays; D008826:Microbial Sensitivity Tests; D058928:Riboswitch; D013295:Streptococcus mutans / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D058928:Riboswitch; D005459:Fluorides