Nelson James W, Plummer Mark S, Blount Kenneth F, Ames Tyler D, Breaker Ronald R
Department of Chemistry, Yale University, New Haven, CT 06520, USA.
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
Chem Biol. 2015 Apr 23;22(4):527-534. doi: 10.1016/j.chembiol.2015.03.016.
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.
氟化物是一种普遍存在的阴离子，可抑制多种代谢过程。在此，我们报告了一系列能增强大肠杆菌和变形链球菌中氟化物毒性的化合物的鉴定结果。这些分子是通过高通量筛选（HTS）分离得到的，该筛选针对的是能通过氟化物核糖开关报告基因融合构建体测定增加细胞内氟化物水平的化合物。合成了一系列衍生物以研究构效关系，从而鉴定出活性得到改善的化合物。因此，我们证明可以通过利用天然氟化物核糖开关，从现有的化学文库中通过高通量筛选鉴定出小分子氟化物毒性激动剂。此外，我们的研究结果表明，某些分子与氟化物联合使用时，可能会进一步优化以用作二元抗菌剂。
