Small molecule fluoride toxicity agonists

Chem Biol. 2015 Apr 23;22(4):527-534. doi: 10.1016/j.chembiol.2015.03.016.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology
  • Escherichia coli / drug effects
  • Fluorides / agonists
  • Fluorides / chemistry*
  • Fluorides / toxicity*
  • High-Throughput Screening Assays
  • Microbial Sensitivity Tests
  • Riboswitch
  • Streptococcus mutans / drug effects
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Riboswitch
  • Fluorides