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Auranofin disrupts selenium metabolism in Clostridium difficile by forming a stable Au–Se adduct

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Abstract

Clostridium difficile is a nosocomial pathogen whose incidence and importance are on the rise. Previous work in our laboratory characterized the central role of selenoenzyme-dependent Stickland reactions in C. difficile metabolism. In this work we have identified, using mass spectrometry, a stable complex formed upon reaction of auranofin (a gold-containing drug) with selenide in vitro. X-ray absorption spectroscopy supports the structure that we proposed on the basis of mass-spectrometric data. Auranofin potently inhibits the growth of C. difficile but does not similarly affect other clostridia that do not utilize selenoproteins to obtain energy. Moreover, auranofin inhibits the incorporation of radioisotope selenium (75Se) in selenoproteins in both Escherichia coli, the prokaryotic model for selenoprotein synthesis, and C. difficile without impacting total protein synthesis. Auranofin blocks the uptake of selenium and results in the accumulation of the auranofin–selenide adduct in the culture medium. Addition of selenium in the form of selenite or l-selenocysteine to the growth medium significantly reduces the inhibitory action of auranofin on the growth of C. difficile. On the basis of these results, we propose that formation of this complex and the subsequent deficiency in available selenium for selenoprotein synthesis is the mechanism by which auranofin inhibits C. difficile growth. This study demonstrates that targeting selenium metabolism provides a new avenue for antimicrobial development against C. difficile and other selenium-dependent pathogens.

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Acknowledgments

The authors thank Michel Warny (Acambis, Cambridge, MA, USA) for providing C. difficile NAPI/027. We also thank August Böck (University of Munich, Munich, Germany) for providing E. coli strain WL400 (selD). The Au compounds used as models were generous gifts from Susan Miller, University of California San Francisco. XAS work in the Scott group is supported by a grant from the National Institutes of Health (GM042025). Portions of this research were carried out at the Stanford Synchrotron Radiation Laboratory, a national user facility operated by Stanford University on behalf of the US Department of Energy, Office of Basic Energy Sciences. The Stanford Synchrotron Radiation Laboratory Structural Molecular Biology Program is supported by the Department of Energy, Office of Biological and Environmental Research, and by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program. This work was supported in part by the Intramural Research Program of the National Institutes of Health (NHLBI). This work was also supported in part by grants to W.T.S. from the Florida Department of Health (05-NIR-10) and the National Institutes of Health (ES01434).

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Authors and Affiliations

  1. Burnett School of Biomedical Science, College of Medicine, University of Central Florida, 4000 Central Florida Boulevard, Building 20, Room 124, Orlando, FL, 32816-2364, USA

    Sarah Jackson-Rosario, Andrew Myers, Rebecca Tarrien & William Thomas Self

  2. Departments of Chemistry and Biochemistry and Molecular Biology, Fred C. Davison Life Sciences Complex, University of Georgia, 1001 Cedar Street, Athens, GA, 30602, USA

    Darin Cowart & Robert A. Scott

  3. Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, 50 South Drive, Bethesda, MD, 20892, USA

    Rodney L. Levine

Authors
  1. Sarah Jackson-Rosario
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  2. Darin Cowart
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  3. Andrew Myers
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  4. Rebecca Tarrien
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  5. Rodney L. Levine
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  6. Robert A. Scott
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  7. William Thomas Self
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Correspondence to William Thomas Self.

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Jackson-Rosario, S., Cowart, D., Myers, A. et al. Auranofin disrupts selenium metabolism in Clostridium difficile by forming a stable Au–Se adduct. J Biol Inorg Chem 14, 507–519 (2009). https://doi.org/10.1007/s00775-009-0466-z

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  • DOI: https://doi.org/10.1007/s00775-009-0466-z

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