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Repurposing auranofin as a Clostridioides difficile therapeutic.
J Antimicrob Chemother. 2020 02 01; 75(2):409-417.JA

Abstract

BACKGROUND

Clostridioides difficile (previously Clostridium difficile) is the leading cause of nosocomial, antibiotic-associated diarrhoea worldwide. Currently, the gold standard of treatment for C. difficile infection (CDI) is vancomycin or metronidazole, although these antibiotics also perturb the protective resident microbiota, often resulting in disease relapse. Thus, an urgent need remains for the development of new treatment strategies. Auranofin is an FDA-approved oral antirheumatic drug that was previously shown to inhibit C. difficile vegetative cell growth, toxin production and spore production in vitro.

OBJECTIVES

To determine the efficacy of auranofin as a CDI therapeutic by examining the effect of treatment on toxin and spore production in vitro and in vivo, and on disease outcomes in mice.

METHODS

C. difficile cultures were treated with auranofin and examined for effects on sporulation and toxin production by sporulation assay and ELISA, respectively. Mice were pretreated with auranofin prior to infection with C. difficile and monitored for physiological conditions, survival and gut damage compared with control animals. Faeces from mice were analysed to determine whether auranofin reduces sporulation and toxin production in vivo.

RESULTS

Auranofin significantly reduces sporulation and toxin production under in vitro conditions and in infected mice in vivo. Mice treated with auranofin lost less weight, displayed a significant increase in survival rates and had significantly less toxin-mediated damage in their colon and caecum compared with control mice.

CONCLUSIONS

Auranofin shows promise as a prospective therapeutic option for C. difficile infections.

Authors+Show Affiliations

Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, 3800, Australia.Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, 3800, Australia.Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, 3800, Australia.Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, 3800, Australia.School of Medicine, Deakin University, Pigdons Road, Waurn Ponds, Victoria, 3216, Australia.Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, 3800, Australia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31642901

Citation

Hutton, Melanie L., et al. "Repurposing Auranofin as a Clostridioides Difficile Therapeutic." The Journal of Antimicrobial Chemotherapy, vol. 75, no. 2, 2020, pp. 409-417.
Hutton ML, Pehlivanoglu H, Vidor CJ, et al. Repurposing auranofin as a Clostridioides difficile therapeutic. J Antimicrob Chemother. 2020;75(2):409-417.
Hutton, M. L., Pehlivanoglu, H., Vidor, C. J., James, M. L., Thomson, M. J., & Lyras, D. (2020). Repurposing auranofin as a Clostridioides difficile therapeutic. The Journal of Antimicrobial Chemotherapy, 75(2), 409-417. https://doi.org/10.1093/jac/dkz430
Hutton ML, et al. Repurposing Auranofin as a Clostridioides Difficile Therapeutic. J Antimicrob Chemother. 2020 02 1;75(2):409-417. PubMed PMID: 31642901.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Repurposing auranofin as a Clostridioides difficile therapeutic. AU - Hutton,Melanie L, AU - Pehlivanoglu,Havva, AU - Vidor,Callum J, AU - James,Meagan L, AU - Thomson,Melanie J, AU - Lyras,Dena, PY - 2019/06/10/received PY - 2019/09/12/revised PY - 2019/09/18/accepted PY - 2019/10/24/pubmed PY - 2019/10/24/medline PY - 2019/10/24/entrez SP - 409 EP - 417 JF - The Journal of antimicrobial chemotherapy JO - J. Antimicrob. Chemother. VL - 75 IS - 2 N2 - BACKGROUND: Clostridioides difficile (previously Clostridium difficile) is the leading cause of nosocomial, antibiotic-associated diarrhoea worldwide. Currently, the gold standard of treatment for C. difficile infection (CDI) is vancomycin or metronidazole, although these antibiotics also perturb the protective resident microbiota, often resulting in disease relapse. Thus, an urgent need remains for the development of new treatment strategies. Auranofin is an FDA-approved oral antirheumatic drug that was previously shown to inhibit C. difficile vegetative cell growth, toxin production and spore production in vitro. OBJECTIVES: To determine the efficacy of auranofin as a CDI therapeutic by examining the effect of treatment on toxin and spore production in vitro and in vivo, and on disease outcomes in mice. METHODS: C. difficile cultures were treated with auranofin and examined for effects on sporulation and toxin production by sporulation assay and ELISA, respectively. Mice were pretreated with auranofin prior to infection with C. difficile and monitored for physiological conditions, survival and gut damage compared with control animals. Faeces from mice were analysed to determine whether auranofin reduces sporulation and toxin production in vivo. RESULTS: Auranofin significantly reduces sporulation and toxin production under in vitro conditions and in infected mice in vivo. Mice treated with auranofin lost less weight, displayed a significant increase in survival rates and had significantly less toxin-mediated damage in their colon and caecum compared with control mice. CONCLUSIONS: Auranofin shows promise as a prospective therapeutic option for C. difficile infections. SN - 1460-2091 UR - https://www.unboundmedicine.com/medline/citation/31642901/Repurposing_auranofin_as_a_Clostridioides_difficile_therapeutic_ L2 - https://academic.oup.com/jac/article-lookup/doi/10.1093/jac/dkz430 DB - PRIME DP - Unbound Medicine ER -
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