title: A small-molecule antivirulence agent for treating Clostridium difficile infection.
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.
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA.
authors.forename: Kristina Oresic
authors.initials: KO
authors.lastname: Bender
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Garland
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5124, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Ferreyra
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5124, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hryckowian
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Child
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Puri
authors.affiliation: Stanford University High-Throughput Bioscience Center, 1291 Welch Road, Stanford, CA 94305-5174, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Solow-Cordero
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5124, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Higginbottom
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA.
authors.forename: Ehud
authors.initials: E
authors.lastname: Segal
authors.affiliation: 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.
authors.forename: Niaz
authors.initials: N
authors.lastname: Banaei
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Aimee
authors.initials: A
authors.lastname: Shen
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5124, USA.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Sonnenburg
authors.affiliation: 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001393:Azoles / Q000627:therapeutic use; D016360:Clostridioides difficile / Q000302:isolation & purification*; D003015:Clostridium Infections / Q000188:drug therapy*; D054833:Isoindoles; D051379:Mice; D016566:Organoselenium Compounds / Q000627:therapeutic use; D014774:Virulence / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen