Small Molecule Inhibitor Screen Reveals Calcium Channel Signaling as a Mechanistic Mediator of Clostridium difficile TcdB-Induced Necrosis.,ACS Chemical Biology

当前位置： X-MOL 学术 › ACS Chem. Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Small Molecule Inhibitor Screen Reveals Calcium Channel Signaling as a Mechanistic Mediator of Clostridium difficile TcdB-Induced Necrosis.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-01-14 , DOI: 10.1021/acschembio.9b00906
Melissa A Farrow ₁ , Nicole M Chumber ₁ , Sarah C Bloch ₁ , McKenzie King ₁ , Kaycei Moton-Melancon ₁ , John Shupe ₁ , Mary K Washington ₁ , Benjamin W Spiller _{1,

2} , D Borden Lacy _{1,

3}

Affiliation

Clostridioides difficile is the leading cause of nosocomial diarrhea in the United States. The primary virulence factors are two homologous glucosyltransferase toxins, TcdA and TcdB, that inactivate host Rho-family GTPases. The glucosyltransferase activity has been linked to a "cytopathic" disruption of the actin cytoskeleton and contributes to the disruption of tight junctions and the production of pro-inflammatory cytokines. TcdB is also a potent cytotoxin that causes epithelium necrotic damage through an NADPH oxidase (NOX)-dependent mechanism. We conducted a small molecule screen to identify compounds that confer protection against TcdB-induced necrosis. We identified an enrichment of "hit compounds" with a dihydropyridine (DHP) core which led to the discovery of a key early stage calcium signal that serves as a mechanistic link between TcdB-induced NOX activation and reactive oxygen species (ROS) production. Disruption of TcdB-induced calcium signaling (with both DHP and non-DHP molecules) is sufficient to ablate ROS production and prevent subsequent necrosis in cells and in a mouse model of intoxication.

中文翻译：

小分子抑制剂筛选揭示了钙通道信号作为艰难梭状芽胞杆菌TcdB诱导的坏死的机制。

艰难梭菌是美国医院腹泻的主要原因。主要的毒力因子是两种同源的葡糖基转移酶毒素TcdA和TcdB，它们使宿主Rho家族GTPases失活。葡糖基转移酶活性与肌动蛋白细胞骨架的“细胞病变”破坏有关，并有助于紧密连接的破坏和促炎性细胞因子的产生。TcdB也是一种有效的细胞毒素，可通过NADPH氧化酶（NOX）依赖性机制引起上皮坏死性损伤。我们进行了一个小分子筛查，以鉴定赋予针对TcdB诱导的坏死的保护作用的化合物。我们发现了丰富的“命中化合物” 带有二氢吡啶（DHP）核，从而发现了关键的早期钙信号，该信号是TcdB诱导的NOX活化与活性氧（ROS）产生之间的机械连接。TcdB诱导的钙信号传导（具有DHP和非DHP分子）的破坏足以消除ROS的产生，并防止随后的细胞和中毒小鼠模型坏死。

更新日期：2020-01-07

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11