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Sci Transl Med. 2015 Sep 23;7(306):306ra148. doi: 10.1126/scitranslmed.aac9103. Epub 2015 Sep 23.

A small-molecule antivirulence agent for treating Clostridium difficile infection.

Author information

1
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA.
2
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5124, USA.
3
Stanford University High-Throughput Bioscience Center, 1291 Welch Road, Stanford, CA 94305-5174, USA.
4
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA. Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5107, USA.
5
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA.
6
Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5124, USA. mbogyo@stanford.edu.

Abstract

Clostridium difficile infection (CDI) is a worldwide health threat that is typically triggered by the use of broad-spectrum antibiotics, which disrupt the natural gut microbiota and allow this Gram-positive anaerobic pathogen to thrive. The increased incidence and severity of disease coupled with decreased response, high recurrence rates, and emergence of multiple antibiotic-resistant strains have created an urgent need for new therapies. We describe pharmacological targeting of the cysteine protease domain (CPD) within the C. difficile major virulence factor toxin B (TcdB). Through a targeted screen with an activity-based probe for this protease domain, we identified a number of potent CPD inhibitors, including one bioactive compound, ebselen, which is currently in human clinical trials for a clinically unrelated indication. This drug showed activity against both major virulence factors, TcdA and TcdB, in biochemical and cell-based studies. Treatment in a mouse model of CDI that closely resembles the human infection confirmed a therapeutic benefit in the form of reduced disease pathology in host tissues that correlated with inhibition of the release of the toxic glucosyltransferase domain (GTD). Our results show that this non-antibiotic drug can modulate the pathology of disease and therefore could potentially be developed as a therapeutic for the treatment of CDI.

PMID:
26400909
PMCID:
PMC6025901
DOI:
10.1126/scitranslmed.aac9103
[Indexed for MEDLINE]
Free PMC Article

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