The Compound U18666A Inhibits the Intoxication of Cells by Clostridioides difficile Toxins TcdA and TcdB
The intestinal pathogen Clostridioides (C.) difficile is a major cause of diarrhea both in hospitals and outpatient in industrialized countries. This bacterium produces two large exotoxins, toxin A (TcdA) and toxin B (TcdB), which are directly responsible for the onset of clinical symptoms of C. dif...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:0c5e3af2c59d40f5bf76f1817af04c772021-12-01T13:49:43ZThe Compound U18666A Inhibits the Intoxication of Cells by Clostridioides difficile Toxins TcdA and TcdB1664-302X10.3389/fmicb.2021.784856https://doaj.org/article/0c5e3af2c59d40f5bf76f1817af04c772021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmicb.2021.784856/fullhttps://doaj.org/toc/1664-302XThe intestinal pathogen Clostridioides (C.) difficile is a major cause of diarrhea both in hospitals and outpatient in industrialized countries. This bacterium produces two large exotoxins, toxin A (TcdA) and toxin B (TcdB), which are directly responsible for the onset of clinical symptoms of C. difficile-associated diseases (CDADs), such as antibiotics-associated diarrhea and the severe, life-threatening pseudomembranous colitis. Both toxins are multidomain proteins and taken up into host eukaryotic cells via receptor-mediated endocytosis. Within the cell, TcdA and TcdB inactivate Rho and/or Ras protein family members by glucosylation, which eventually results in cell death. The cytotoxic mode of action of the toxins is the main reason for the disease. Thus, compounds capable of inhibiting the cellular uptake and/or mode-of-action of both toxins are of high therapeutic interest. Recently, we found that the sterol regulatory element-binding protein 2 (SREBP-2) pathway, which regulates cholesterol content in membranes, is crucial for the intoxication of cells by TcdA and TcdB. Furthermore, it has been shown that membrane cholesterol is required for TcdA- as well as TcdB-mediated pore formation in endosomal membranes, which is a key step during the translocation of the glucosyltransferase domain of both toxins from endocytic vesicles into the cytosol of host cells. In the current study, we demonstrate that intoxication by TcdA and TcdB is diminished in cultured cells preincubated with the compound U18666A, an established inhibitor of cholesterol biosynthesis and/or intracellular transport. U18666A-pretreated cells were also less sensitive against TcdA and TcdB variants from the epidemic NAP1/027 C. difficile strain. Our study corroborates the crucial role of membrane cholesterol for cell entry of TcdA and TcdB, thus providing a valuable basis for the development of novel antitoxin strategies in the context of CDADs.Panagiotis PapatheodorouSelina KindigAdriana Badilla-LoboStephan FischerEbru DurgunTharani ThuraisingamAlexander WitteShuo SongKlaus AktoriesEsteban Chaves-OlarteCésar RodríguezHolger BarthFrontiers Media S.A.articlebacterial toxintoxin inhibitorcholesterol biosynthesischolesterol transportcholesterolMicrobiologyQR1-502ENFrontiers in Microbiology, Vol 12 (2021) |
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bacterial toxin toxin inhibitor cholesterol biosynthesis cholesterol transport cholesterol Microbiology QR1-502 |
| spellingShingle |
bacterial toxin toxin inhibitor cholesterol biosynthesis cholesterol transport cholesterol Microbiology QR1-502 Panagiotis Papatheodorou Selina Kindig Adriana Badilla-Lobo Stephan Fischer Ebru Durgun Tharani Thuraisingam Alexander Witte Shuo Song Klaus Aktories Esteban Chaves-Olarte César Rodríguez Holger Barth The Compound U18666A Inhibits the Intoxication of Cells by Clostridioides difficile Toxins TcdA and TcdB |
| description |
The intestinal pathogen Clostridioides (C.) difficile is a major cause of diarrhea both in hospitals and outpatient in industrialized countries. This bacterium produces two large exotoxins, toxin A (TcdA) and toxin B (TcdB), which are directly responsible for the onset of clinical symptoms of C. difficile-associated diseases (CDADs), such as antibiotics-associated diarrhea and the severe, life-threatening pseudomembranous colitis. Both toxins are multidomain proteins and taken up into host eukaryotic cells via receptor-mediated endocytosis. Within the cell, TcdA and TcdB inactivate Rho and/or Ras protein family members by glucosylation, which eventually results in cell death. The cytotoxic mode of action of the toxins is the main reason for the disease. Thus, compounds capable of inhibiting the cellular uptake and/or mode-of-action of both toxins are of high therapeutic interest. Recently, we found that the sterol regulatory element-binding protein 2 (SREBP-2) pathway, which regulates cholesterol content in membranes, is crucial for the intoxication of cells by TcdA and TcdB. Furthermore, it has been shown that membrane cholesterol is required for TcdA- as well as TcdB-mediated pore formation in endosomal membranes, which is a key step during the translocation of the glucosyltransferase domain of both toxins from endocytic vesicles into the cytosol of host cells. In the current study, we demonstrate that intoxication by TcdA and TcdB is diminished in cultured cells preincubated with the compound U18666A, an established inhibitor of cholesterol biosynthesis and/or intracellular transport. U18666A-pretreated cells were also less sensitive against TcdA and TcdB variants from the epidemic NAP1/027 C. difficile strain. Our study corroborates the crucial role of membrane cholesterol for cell entry of TcdA and TcdB, thus providing a valuable basis for the development of novel antitoxin strategies in the context of CDADs. |
| format |
article |
| author |
Panagiotis Papatheodorou Selina Kindig Adriana Badilla-Lobo Stephan Fischer Ebru Durgun Tharani Thuraisingam Alexander Witte Shuo Song Klaus Aktories Esteban Chaves-Olarte César Rodríguez Holger Barth |
| author_facet |
Panagiotis Papatheodorou Selina Kindig Adriana Badilla-Lobo Stephan Fischer Ebru Durgun Tharani Thuraisingam Alexander Witte Shuo Song Klaus Aktories Esteban Chaves-Olarte César Rodríguez Holger Barth |
| author_sort |
Panagiotis Papatheodorou |
| title |
The Compound U18666A Inhibits the Intoxication of Cells by Clostridioides difficile Toxins TcdA and TcdB |
| title_short |
The Compound U18666A Inhibits the Intoxication of Cells by Clostridioides difficile Toxins TcdA and TcdB |
| title_full |
The Compound U18666A Inhibits the Intoxication of Cells by Clostridioides difficile Toxins TcdA and TcdB |
| title_fullStr |
The Compound U18666A Inhibits the Intoxication of Cells by Clostridioides difficile Toxins TcdA and TcdB |
| title_full_unstemmed |
The Compound U18666A Inhibits the Intoxication of Cells by Clostridioides difficile Toxins TcdA and TcdB |
| title_sort |
compound u18666a inhibits the intoxication of cells by clostridioides difficile toxins tcda and tcdb |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/0c5e3af2c59d40f5bf76f1817af04c77 |
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