Academic Journal
Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues
| العنوان: | Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues |
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| المؤلفون: | Paparella, Ashleigh S., Aboulache, Briana L., Harijan, Rajesh K., Potts, Kathryn S., Tyler, Peter C., Schramm, Vern L. |
| المساهمون: | U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences, U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases |
| المصدر: | Nature Communications ; volume 12, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2021 |
| الوصف: | Clostridium difficile causes life-threatening diarrhea and is the leading cause of healthcare-associated bacterial infections in the United States. TcdA and TcdB bacterial toxins are primary determinants of disease pathogenesis and are attractive therapeutic targets. TcdA and TcdB contain domains that use UDP-glucose to glucosylate and inactivate host Rho GTPases, resulting in cytoskeletal changes causing cell rounding and loss of intestinal integrity. Transition state analysis revealed glucocationic character for the TcdA and TcdB transition states. We identified transition state analogue inhibitors and characterized them by kinetic, thermodynamic and structural analysis. Iminosugars, isofagomine and noeuromycin mimic the transition state and inhibit both TcdA and TcdB by forming ternary complexes with Tcd and UDP, a product of the TcdA- and TcdB-catalyzed reactions. Both iminosugars prevent TcdA- and TcdB-induced cytotoxicity in cultured mammalian cells by preventing glucosylation of Rho GTPases. Iminosugar transition state analogues of the Tcd toxins show potential as therapeutics for C. difficile pathology. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-021-26580-6 |
| الاتاحة: | http://dx.doi.org/10.1038/s41467-021-26580-6 https://www.nature.com/articles/s41467-021-26580-6.pdf https://www.nature.com/articles/s41467-021-26580-6 |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.58BBAC9 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-021-26580-6 |
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