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

1. Michael B. Harbuta,
2. Catherine Vilchèzeb,
3. Xiaozhou Luoc,
4. Mary E. Henslerd,
5. Hui Guoa,
6. Baiyuan Yanga,
7. Arnab K. Chatterjeea,
8. Victor Nizetd,
9. William R. Jacobs, Jr.b,
10. Peter G. Schultza,c,1, and
11. Feng Wanga,1

1. Contributed by Peter G. Schultz, February 27, 2015 (sent for review January 7, 2015)

Significance

The identification of new antibiotics with novel mechanisms of action has become a pressing need considering the growing threat of drug-resistant infections.

We have identified auranofin, an FDA-approved drug, as having potent bactericidal activity against Gram-positive pathogenic bacteria. Auranofin inhibits an enzyme, thioredoxin reductase, not targeted by other antibiotics, and thus retains efficacy against many clinically relevant drug-resistant strains, including in a mouse model of infection.

Because auranofin is an approved drug, its route to the clinic may be expedited with reduced cost. Our work suggests that auranofin is a candidate for drug repurposing in antibacterial therapy.

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.