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Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis.
Proc Natl Acad Sci U S A. 2015 Apr 07; 112(14):4453-8.PN

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+Show Affiliations

California Institute for Biomedical Research, La Jolla, CA 92037;Howard Hughes Medical Institute and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; and.Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093.California Institute for Biomedical Research, La Jolla, CA 92037;California Institute for Biomedical Research, La Jolla, CA 92037;California Institute for Biomedical Research, La Jolla, CA 92037;Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093.Howard Hughes Medical Institute and Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;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.California Institute for Biomedical Research, La Jolla, CA 92037; schultz@scripps.edu fwang@calibr.org.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25831516

Citation

Harbut, Michael B., et al. "Auranofin Exerts Broad-spectrum Bactericidal Activities By Targeting Thiol-redox Homeostasis." Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 14, 2015, pp. 4453-8.
Harbut MB, Vilchèze C, Luo X, et al. Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis. Proc Natl Acad Sci USA. 2015;112(14):4453-8.
Harbut, M. B., Vilchèze, C., Luo, X., Hensler, M. E., Guo, H., Yang, B., Chatterjee, A. K., Nizet, V., Jacobs, W. R., Schultz, P. G., & Wang, F. (2015). Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 112(14), 4453-8. https://doi.org/10.1073/pnas.1504022112
Harbut MB, et al. Auranofin Exerts Broad-spectrum Bactericidal Activities By Targeting Thiol-redox Homeostasis. Proc Natl Acad Sci USA. 2015 Apr 7;112(14):4453-8. PubMed PMID: 25831516.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis. AU - Harbut,Michael B, AU - Vilchèze,Catherine, AU - Luo,Xiaozhou, AU - Hensler,Mary E, AU - Guo,Hui, AU - Yang,Baiyuan, AU - Chatterjee,Arnab K, AU - Nizet,Victor, AU - Jacobs,William R,Jr AU - Schultz,Peter G, AU - Wang,Feng, Y1 - 2015/03/23/ PY - 2015/4/2/entrez PY - 2015/4/2/pubmed PY - 2015/6/30/medline KW - Gram-positive KW - MRSA KW - auranofin KW - tuberculosis SP - 4453 EP - 8 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 112 IS - 14 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/25831516/Auranofin_exerts_broad_spectrum_bactericidal_activities_by_targeting_thiol_redox_homeostasis_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=25831516 DB - PRIME DP - Unbound Medicine ER -