Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis

Michael B. Harbut, Catherine Vilchèze, Xiaozhou Luo, Mary E. Hensler, Hui Guo, Baiyuan Yang, Arnab K. Chatterjee, Victor Nizet, William R. Jacobs, Peter G. Schultz, Feng Wang

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Infections caused by antibiotic-resistant bacteria are a rising public health threat and make the identification of new antibiotics a priority. From a cell-based screen for bactericidal compounds against Mycobacterium tuberculosis under nutrient-deprivation conditions we identified auranofin, an orally bioavailable FDA-approved antirheumatic drug, as having potent bactericidal activities against both replicating and nonreplicating M. tuberculosis. We also found that auranofin is active against other Gram-positive bacteria, including Bacillus subtilis and Enterococcus faecalis, and drug-sensitive and drug-resistant strains of Enterococcus faecium and Staphylococcus aureus. Our biochemical studies showed that auranofin inhibits the bacterial thioredoxin reductase, a protein essential in many Gram-positive bacteria for maintaining the thiol-redox balance and protecting against reactive oxidative species. Auranofin decreases the reducing capacity of target bacteria, thereby sensitizing them to oxidative stress. Finally, auranofin was efficacious in a murine model of methicillin-resistant S. aureus infection. These results suggest that the thioredoxin-mediated redox cascade of Gram-positive pathogens is a valid target for the development of antibacterial drugs, and that the existing clinical agent auranofin may be repurposed to aid in the treatment of several important antibiotic-resistant pathogens.

Original languageEnglish (US)
Pages (from-to)4453-4458
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number14
DOIs
StatePublished - Apr 7 2015

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Keywords

  • Auranofin
  • Gram-positive
  • MRSA
  • Tuberculosis

ASJC Scopus subject areas

  • General

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