Unknown

Dataset Information

0

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


ABSTRACT: 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.

SUBMITTER: Farrow MA 

PROVIDER: S-EPMC7230009 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

Small Molecule Inhibitor Screen Reveals Calcium Channel Signaling as a Mechanistic Mediator of <i>Clostridium difficile</i> TcdB-Induced Necrosis.

Farrow Melissa A MA   Chumber Nicole M NM   Bloch Sarah C SC   King McKenzie M   Moton-Melancon Kaycei K   Shupe John J   Washington Mary K MK   Spiller Benjamin W BW   Lacy D Borden DB  

ACS chemical biology 20200114 5


<i>Clostridioides difficile</i> 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 necroti  ...[more]

Similar Datasets

2018-05-31 | GSE110242 | GEO
| S-EPMC4944984 | biostudies-literature
| S-EPMC6386544 | biostudies-literature
| S-EPMC8560925 | biostudies-literature
| S-EPMC6796971 | biostudies-literature
| S-EPMC4460460 | biostudies-literature
| S-EPMC2924371 | biostudies-literature
| S-EPMC9024770 | biostudies-literature
| S-EPMC4062579 | biostudies-literature
| S-EPMC3005307 | biostudies-literature