Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues

Paparella, Ashleigh S.; Aboulache, Briana L.; Harijan, Rajesh K.; Potts, Kathryn S.; Tyler, Peter C.; Schramm, Vern L.

doi:10.1038/s41467-021-26580-6

Title: Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues

Journal Article · Mon Nov 01 00:00:00 EDT 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-26580-6· OSTI ID:1829876

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^[2]; Harijan, Rajesh K. ^[1];

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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)

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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Brookhaven National Lab. (BNL), Upton, NY (United States)

Sponsoring Organization:: 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)

Grant/Contract Number:: AC02-06CH11357; SC0012704; P30GM133893; GM041916; AI150971; S10 OD020068

OSTI ID:: 1829876

Alternate ID(s):: OSTI ID: 1875645

Report Number(s):: BNL-223143-2022-JACI; APS_263792

Journal Information:: Nature Communications, Vol. 12, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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