A new class of inhibitors of the AraC family virulence regulator Vibrio cholerae ToxT.
A new class of inhibitors of the AraC family virulence regulator Vibrio cholerae ToxT.
复制标题
AraC 家族毒力调节剂霍乱弧菌 ToxT 的一类新抑制剂。
DOI：
10.1038/srep45011
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发表时间：
2017
影响因子：
4.6
通讯作者：
Kull,FJon
中科院分区：
文献类型：
--
作者：
Woodbrey,AnneK;Onyango,EvansO;Pellegrini,Maria;Kovacikova,Gabriela;Taylor,RonaldK;Gribble,GordonW;Kull,FJon
霍乱弧菌是导致霍乱的罪魁祸首，霍乱感染了全世界数百万人。虽然有预防霍乱的疫苗，口服补液疗法也是一种有效的治疗方法，但在改善卫生条件和获得清洁水等长期解决办法普及之前，霍乱仍将是一个全球健康威胁。正因为如此，迫切需要有效的治疗方法，可以减轻霍乱症状，或采取预防措施，以防止霍乱感染的毒力影响。在这里，我们报告的设计，合成和表征的一组化合物，结合和抑制ToxT，转录因子，直接调节两个primaryV。霍乱毒力因子使用在ToxT的X射线结构中观察到的单不饱和脂肪酸的折叠结构作为模板，我们设计了十种新型化合物，其抑制毒性级联的程度比任何已知的抑制剂都要大。我们的研究结果为开发可行的抗霍乱和潜在的其他形式的细菌致病性疾病的抗毒力疗法提供了结构和功能基础。
Vibrio choleraeis responsible for the diarrheal disease cholera that infects millions of people worldwide. While vaccines protecting against cholera exist, and oral rehydration therapy is an effective treatment method, the disease will remain a global health threat until long-term solutions such as improved sanitation and access to clean water become widely available. Because of this, there is a pressing need for potent therapeutics that can either mitigate cholera symptoms, or act prophylactically to prevent the virulent effects of a cholera infection. Here we report the design, synthesis, and characterization of a set of compounds that bind and inhibit ToxT, the transcription factor that directly regulates the two primaryV. choleraevirulence factors. Using the folded structure of the monounsaturated fatty acid observed in the X-ray structure of ToxT as a template, we designed ten novel compounds that inhibit the virulence cascade to a greater degree than any known inhibitor. Our findings provide a structural and functional basis for the development of viable antivirulence therapeutics that combat cholera and, potentially, other forms of bacterial pathogenic disease.