Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues
Abstract
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.
- Authors:
-
- Albert Einstein College of Medicine, Bronx, NY (United States)
- Albert Einstein College of Medicine, Bronx, NY (United States); Univ. of Colorado, Boulder, CO (United States)
- Victoria Univ. of Wellington, Lower Hutt (New Zealand)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health, National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1829876
- Alternate Identifier(s):
- OSTI ID: 1875645
- Report Number(s):
- BNL-223143-2022-JACI
Journal ID: ISSN 2041-1723; APS_263792
- Grant/Contract Number:
- AC02-06CH11357; SC0012704; P30GM133893; GM041916; AI150971; S10 OD020068
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 12; Journal Issue: 1; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 99 GENERAL AND MISCELLANEOUS; Enzymes; Transferases; X-ray crystallography
Citation Formats
Paparella, Ashleigh S., Aboulache, Briana L., Harijan, Rajesh K., Potts, Kathryn S., Tyler, Peter C., and Schramm, Vern L. Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues. United States: N. p., 2021.
Web. doi:10.1038/s41467-021-26580-6.
Paparella, Ashleigh S., Aboulache, Briana L., Harijan, Rajesh K., Potts, Kathryn S., Tyler, Peter C., & Schramm, Vern L. Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues. United States. https://doi.org/10.1038/s41467-021-26580-6
Paparella, Ashleigh S., Aboulache, Briana L., Harijan, Rajesh K., Potts, Kathryn S., Tyler, Peter C., and Schramm, Vern L. Mon .
"Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues". United States. https://doi.org/10.1038/s41467-021-26580-6. https://www.osti.gov/servlets/purl/1829876.
@article{osti_1829876,
title = {Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues},
author = {Paparella, Ashleigh S. and Aboulache, Briana L. and Harijan, Rajesh K. and Potts, Kathryn S. and Tyler, Peter C. and Schramm, Vern L.},
abstractNote = {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.},
doi = {10.1038/s41467-021-26580-6},
journal = {Nature Communications},
number = 1,
volume = 12,
place = {United States},
year = {Mon Nov 01 00:00:00 EDT 2021},
month = {Mon Nov 01 00:00:00 EDT 2021}
}
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