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

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 ora...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 14; p. 4453
Main Authors: Harbut, Michael B, Vilchèze, Catherine, Luo, Xiaozhou, Hensler, Mary E, Guo, Hui, Yang, Baiyuan, Chatterjee, Arnab K, Nizet, Victor, Jacobs, Jr, William R, Schultz, Peter G, Wang, Feng
Format: Journal Article
Language:English
Published: United States 07.04.2015
Subjects:
Animals
Anti-Bacterial Agents - chemistry
Auranofin - chemistry
Bacillus subtilis - drug effects
Bacterial Proteins - chemistry
Dose-Response Relationship, Drug
Enterococcus faecium - drug effects
Female
Gene Deletion
Glutathione - chemistry
Homeostasis
Mice
Microbial Sensitivity Tests
Mycobacterium tuberculosis - drug effects
Oxidation-Reduction
Oxidative Stress
Staphylococcus aureus - drug effects
Stem Cells
Sulfhydryl Compounds - chemistry
Thioredoxin-Disulfide Reductase - chemistry
auranofin
Gram-positive
MRSA
tuberculosis
ISSN:1091-6490, 1091-6490
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Summary: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1504022112