Inhibition of Bacterial and Fungal Pathogens by the Orphaned Drug Auranofin

Fuchs, Beth Burgwyn; Rajaraman, Rajmohan; Souza, Ana Carolina Remondi; Eatemadpour, Soraya; Rossoni, Rodnei Dennis; Santos, Danielle Anjos dos; Junqueira, Juliana Campos; Rice, Louis B.; Mylonakis, Eleftherios

doi:10.4155/fmc.15.182

Cited by 54 publications

(65 citation statements)

References 38 publications

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“…Recent studies, including the present work, demonstrate that auranofin inhibits the planktonic growth of multiple species of fungi including C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, C. neoformans , and C. gattii with an average MIC of 4 μg/ml (Stylianou et al, 2014; Fuchs et al, 2016). …”

Section: Discussionsupporting

confidence: 51%

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Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

Thangamani

Maland

Mohammad

et al. 2017

Front. Cell. Infect. Microbiol.

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Current antifungal therapies have limited effectiveness in treating invasive fungal infections. Furthermore, the development of new antifungal is currently unable to keep pace with the urgent demand for safe and effective new drugs. Auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, inhibits growth of a diverse array of clinical isolates of fungi and represents a new antifungal agent with a previously unexploited mechanism of action. In addition to auranofin's potent antifungal activity against planktonic fungi, this drug significantly reduces the metabolic activity of Candida cells encased in a biofilm. Unbiased chemogenomic profiling, using heterozygous S. cerevisiae deletion strains, combined with growth assays revealed three probable targets for auranofin's antifungal activity—mia40, acn9, and coa4. Mia40 is of particular interest given its essential role in oxidation of cysteine rich proteins imported into the mitochondria. Biochemical analysis confirmed auranofin targets the Mia40-Erv1 pathway as the drug inhibited Mia40 from interacting with its substrate, Cmc1, in a dose-dependent manner similar to the control, MB-7. Furthermore, yeast mitochondria overexpressing Erv1 were shown to exhibit resistance to auranofin as an increase in Cmc1 import was observed compared to wild-type yeast. Further in vivo antifungal activity of auranofin was examined in a Caenorhabditis elegans animal model of Cryptococcus neoformans infection. Auranofin significantly reduced the fungal load in infected C. elegans. Collectively, the present study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antifungal agent and may offer a safe, effective, and quick supplement to current approaches for treating fungal infections.

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Section: Discussionsupporting

confidence: 51%

“…Recent studies by Fuchs et al (2016) and Stylianou et al (2014) reported that auranofin also possesses antifungal activity. However, the antifungal MOA and in vivo antifungal efficacy of auranofin remain unclear with several possible targets reported.…”

Section: Introductionmentioning

confidence: 99%

Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

Thangamani

Maland

Mohammad

et al. 2017

Front. Cell. Infect. Microbiol.

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“…57 Likewise, recombinant CaTrxR protein induced high levels of serum specific antibodies and reduced the fungal burden in experimental disseminated candidiasis in mice. 58 In addition, recent studies on the thioredoxin reductase inhibitor auranofin 59 highlighted its promising antimicrobial potential against various bacteria, [60][61][62][63] as well as some pathogenic yeasts 61,64 and filamentous fungi. 64 Finally, our experiments also showed overexpression of the flavohemoglobin gene SAPIO CDS8682 and the nitrite reductase gene SAPIO CDS10292 upon exposure to DETA-NO.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling ofScedosporium apiospermumenzymatic antioxidant gene battery unravels the involvement of thioredoxin reductases against chemical and phagocytic cells oxidative stress

et al. 2018

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Scedosporium species rank the second, after Aspergillus fumigatus, among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF). Development of microorganisms in the respiratory tract depends on their capacity to evade killing by the host immune system, particularly through the oxidative response of macrophages and neutrophils, with the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). This is particularly true in the airways of CF patients which display an exacerbated inflammatory reaction. To protect themselves, pathogens have developed various enzymatic antioxidant systems implicated in ROS degradation, including superoxide dismutases, catalases, cytochrome C peroxidases, chloroperoxidases and enzymes of the glutathione and thioredoxin systems, or in RNS degradation, that is, flavohemoglobins, nitrate reductases, and nitrite reductases. Here we investigated the transcriptional regulation of the enzymatic antioxidant gene battery in 24-h-old hyphae of Scedosporium apiospermum in response to oxidative stress induced chemically or by exposure to activated phagocytic cells. We showed that 21 out of the 33 genes potentially implicated in the oxidative or nitrosative stress response were overexpressed upon exposure of the fungus to various chemical oxidants, while they were only 13 in co-cultures with macrophages or neutrophils. Among them, genes encoding two thioredoxin reductases and to a lesser extent, a peroxiredoxin and one catalase were found to be overexpressed after chemical oxidative stress as well as in co-cultures. These results suggest that thioredoxin reductases, which are known to be virulence factors in other pathogenic fungi, play a key role in pathogenesis of scedosporiosis, and may be new drug targets.

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“…Our focus in one of these targets, TRR1, has already resulted in the discovery of new small molecule antifungal candidates (Abadio et al, 2015). TRR1 might also be a target for auranofin, an antirheumatic drug that displayed interesting properties in studies that aimed to repurpose it as an antifungal (Siles et al, 2013;Fuchs et al, 2016;Thangamani et al, 2017;Wiederhold et al, 2017). In this work we made the first steps in validating this target for antibody-based therapies as well.…”

Section: Discussionmentioning

confidence: 99%

Thioredoxin Reductase 1 Is a Highly Immunogenic Cell Surface Antigen in Paracoccidioides spp., Candida albicans, and Cryptococcus neoformans

et al. 2020

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Inhibition of Bacterial and Fungal Pathogens by the Orphaned Drug Auranofin

Cited by 54 publications

References 38 publications

Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway

Transcriptional profiling ofScedosporium apiospermumenzymatic antioxidant gene battery unravels the involvement of thioredoxin reductases against chemical and phagocytic cells oxidative stress

Thioredoxin Reductase 1 Is a Highly Immunogenic Cell Surface Antigen in Paracoccidioides spp., Candida albicans, and Cryptococcus neoformans

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