title: Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis.
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.
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Michael B
authors.initials: MB
authors.lastname: Harbut
authors.affiliation: Howard Hughes Medical Institute and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Catherine
authors.initials: C
authors.lastname: Vilchèze
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hensler
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Baiyuan
authors.initials: B
authors.lastname: Yang
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037;
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.affiliation: Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Howard Hughes Medical Institute and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037; Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; and schultz@scripps.edu fwang@calibr.org.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: California Institute for Biomedical Research, La Jolla, CA 92037; schultz@scripps.edu fwang@calibr.org.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001310:Auranofin / Q000737:chemistry*; D001412:Bacillus subtilis / Q000187:drug effects; D001426:Bacterial Proteins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D016984:Enterococcus faecium / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D005978:Glutathione / Q000737:chemistry; D006706:Homeostasis; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D013211:Staphylococcus aureus / Q000187:drug effects; D013234:Stem Cells; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013880:Thioredoxin-Disulfide Reductase / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D013438:Sulfhydryl Compounds; D001310:Auranofin; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione
keywords: Gram-positive; MRSA; auranofin; tuberculosis
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