Evidence that the antiproliferative effects of auranofin in Saccharomyces cerevisiae arise from inhibition of mitochondrial respiration

Gamberi, Tania; Fiaschi, Tania; Modesti, Alessandra; Massai, Lara; Messori, Luigi; Balzi, Manuela; Magherini, Francesca

doi:10.1016/j.biocel.2015.05.016

Cited by 14 publications

(20 citation statements)

References 51 publications

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“…These results are in agreement with Gamberi's et al (2015) results in that mitochondrial function appears to be a target of auranofin. It should be noted that Gamberi et al used haploid deletion strains sensitivity, which generally does not inform on the direct target of a compound as opposed to the heterozygous deletion strains used in our study.…”

Section: Resultssupporting

confidence: 93%

“…On the other hand, genes ( rad18 Δ and nsi1 Δ) involved in chromatin function were found to not be affected possibly because of the concentration used in our validation studies or because they may be false positives from the profiling data. Our results are in agreement with Gamberi et al (2015) indicating the mitochondrial protein(s) is the potential target of auranofin. We further confirmed the three heterozygous deletion strains ( mia40 Δ, acn9 Δ, and coa4 Δ) were sensitive to auranofin when grown in YPD liquid medium with auranofin.…”

Section: Discussionsupporting

confidence: 94%

“…Comparison of Lee et al's results with our 85 strains showed that two strains, rho1 Δ and mia40 Δ, overlapped between the data sets (Figure 3E). An additional study by Gamberi et al (2015) specifically assessed sensitivity and resistance of haploid deletion strains involved in mitochondrial function and found them to be differentially effects to auranofin compared to the haploid wild type parental strain. Based on studies by Gamberi et al (2015) and Lee et al (2014), we next moved to examine sensitivity of the corresponding heterozygous deletion strains involved in mitochondrial function and redox homeostasis that are possibly sensitive to auranofin.…”

Section: Resultsmentioning

confidence: 99%

“…To assess growth on solid medium, 5 μL of ten-fold diluted yeast cells were spotted onto YPD agar containing DMSO or auranofin (6.25 μg/mL). Growth of yeast strains was monitored after incubating the plates for 48 h, as described elsewhere (Gamberi et al, 2015). …”

Section: Methodsmentioning

confidence: 99%

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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: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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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“…After 24 hours of incubation, yeast growth was monitored using a spectrophotometer (OD 600 ) and the results were expressed as percent growth rate for each strain compared to the untreated control group, as described elsewhere [37]. …”

Section: Methodsmentioning

confidence: 99%

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells

Thangamani

Eldesouky

Mohammad

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Ebselen, an organoselenium compound and a clinically safe molecule has been reported to possess potent antifungal activity, but its antifungal mechanism of action and in vivo antifungal activity remains unclear. Methods The antifungal effect of ebselen was tested against Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, Cryptococcus neoformans, and C. gattii clinical isolates. Chemogenomic profiling and biochemical assays were employed to identify the antifungal target of ebselen. Ebselen’s antifungal activity in vivo was investigated in a Caenorhabditis elegans animal model. Results Ebselen exhibits potent antifungal activity against both Candida spp. and Cryptococcus spp, at concentrations ranging from 0.5 – 2 μg/ml. Ebselen rapidly eradicates a high fungal inoculum within two hours of treatment. Investigation of the drug’s antifungal mechanism of action indicates that ebselen depletes intracellular glutathione (GSH) levels, leading to increased production of reactive oxygen species (ROS), and thereby disturbs the redox homeostasis in fungal cells. Examination of ebselen’s in vivo antifungal activity in two Caenorhabditis elegans models of infection demonstrate that ebselen is superior to conventional antifungal drugs (fluconazole, flucytosine and amphotericin) in reducing Candida and Cryptococcus fungal load. Conclusion Ebselen possesses potent antifungal activity against clinically relevant isolates of both Candida and Cryptococcus by regulating GSH and ROS production. The potent in vivo antifungal activity of ebselen supports further investigation for repurposing it for use as an antifungal agent. General significance The present study shows that ebselen targets glutathione and also support that glutathione as a potential target for antifungal drug development.

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Target‐based drug repurposing against Candida albicans—A computational modeling, docking, and molecular dynamic simulations study

Verma

Pradhan

Nayek

et al. 2021

J of Cellular Biochemistry

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The emergence of multidrug‐resistant strains of Candida albicans has become a global threat mostly due to co‐infection with immune‐compromised patients leading to invasive candidiasis. The life‐threatening form of the disease can be managed quickly and effectively by drug repurposing. Thus, the study used in silico approaches to evaluate Food and Drug Administration (FDA) approved drugs against three drug targets—TRR1, TOM40, and YHB1. The tertiary structures of three drug targets were modeled, refined, and evaluated for their structural integrity based on PROCHECK, ERRAT, and PROSA. High‐throughput virtual screening of FDA‐approved drugs (8815), interaction analysis, and energy profiles had revealed that DB01102 (Arbutamine), DB01611 (Hydroxychloroquine), and DB09319 (Carindacillin) exhibited better binding affinity with TRR1, TOM40, and YHB1, respectively. Notably, the molecular dynamic simulation explored that Gln45, Thr119, and Asp288 of TRR1; Thr107 and Ser121 of TOM40; Arg193, Glu213, and Ser228 of YHB1 are crucial residues for stable drug‐target interaction. Additionally, it also prioritized Arbutamine‐TRR1 as the best drug‐target complex based on MM‐PBSA (−52.72 kcal/mol), RMSD (2.43 Å), and radius of gyration (−21.49 Å) analysis. In‐depth, PCA results supported the findings of molecular dynamic simulations. Interestingly, the conserved region (>70%) among the TRR1 sequences from pathogenic Candida species indicated the effectiveness of Arbutamine against multiple species of Candida as well. Thus, the study dispenses new insight and enriches the understanding of developing an advanced technique to consider potential antifungals against C. albicans. Nonetheless, a detailed experimental validation is needed to investigate the efficacy of Arbutamin against life‐threatening candidiasis.

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Evidence that the antiproliferative effects of auranofin in Saccharomyces cerevisiae arise from inhibition of mitochondrial respiration

Cited by 14 publications

References 51 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

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells

Target‐based drug repurposing against Candida albicans—A computational modeling, docking, and molecular dynamic simulations study

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