Small Molecule Inhibitor Screen Reveals Calcium Channel Signaling as a Mechanistic Mediator of Clostridium difficile TcdB-Induced Necrosis
| Autor: | McKenzie King, Melissa A. Farrow, Benjamin W. Spiller, John A. Shupe, Sarah C. Bloch, Kaycei Moton-Melancon, Nicole M. Chumber, D. Borden Lacy, Mary Kay Washington |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Dihydropyridines Virulence Factors Bacterial Toxins Drug Evaluation Preclinical 01 natural sciences Biochemistry Article Proinflammatory cytokine 03 medical and health sciences Mice Necrosis Anti-Infective Agents medicine Animals Humans Calcium Signaling Calcium signaling NADPH oxidase biology Tight junction Dose-Response Relationship Drug 010405 organic chemistry Chemistry Clostridioides difficile Calcium channel Dihydropyridine NADPH Oxidases General Medicine Actin cytoskeleton Calcium Channel Blockers 0104 chemical sciences Cell biology Actin Cytoskeleton Kinetics 030104 developmental biology Glucosyltransferases biology.protein Molecular Medicine Cytokines Glucosyltransferase Calcium Channels Reactive Oxygen Species medicine.drug |
| Zdroj: | ACS Chem Biol |
| Popis: | Clostridioides difficile is the leading cause of nosocomial diarrhea in the United States. The primary virulence factors are two homologous sglucosyltransferase 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. |
| Databáze: | OpenAIRE |
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