Woodbrey Anne K, Onyango Evans O, Kovacikova Gabriela, Kull F Jon, Gribble Gordon W
Department of Chemistry , Dartmouth College , Hanover , New Hampshire 03755 , United States.
Department of Microbiology and Immunology , Geisel School of Medicine at Dartmouth , Hanover , New Hampshire 03755 , United States.
Biochemistry. 2018 Sep 25;57(38):5609-5615. doi: 10.1021/acs.biochem.8b00667. Epub 2018 Sep 12.
We have previously designed and synthesized small-molecule inhibitors that reduce Vibrio cholerae virulence in vitro by targeting the transcription factor ToxT. Here we report the synthesis and biological activity of derivatives of our previous bicyclic, fatty acid-like inhibitors. All of the synthesized derivatives show antivirulence activity in vitro. For the most potent compounds, a concentration of 5 μM completely inhibited ToxT-mediated tcpA expression as measured in the β-galactosidase assay. One indole compound, 3-(1-butyl-1 H-indol-7-yl)propanoic acid (8), was also effective at inhibiting intestinal colonization in the infant mouse. These modified compounds may serve as good candidates for further anti-cholera drug development.
我们之前设计并合成了小分子抑制剂，这些抑制剂通过靶向转录因子ToxT在体外降低霍乱弧菌的毒力。在此，我们报告我们之前的双环、脂肪酸样抑制剂衍生物的合成及生物活性。所有合成的衍生物在体外均显示出抗毒力活性。对于最有效的化合物，在β-半乳糖苷酶测定中，5 μM的浓度可完全抑制ToxT介导的tcpA表达。一种吲哚化合物，3-(1-丁基-1H-吲哚-7-基)丙酸(8)，在抑制幼鼠肠道定殖方面也有效。这些修饰后的化合物可能是进一步开发抗霍乱药物的良好候选物。
