Repurposing Approach Identifies Auranofin with Broad Spectrum Antifungal Activity That Targets Mia40-Erv1 Pathway.
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 ofCandidacells encased in a biofilm. Unbiased chemogenomic profiling, using heterozygousS. cerevisiaedeletion strains, combined with growth assays revealed three probable targets for auranofin's antifungal activity-mia40, acn9, andcoa4. 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. Furtherin vivoantifungal activity of auranofin was examined in aCaenorhabditis elegansanimal model ofCryptococcus neoformansinfection. Auranofin significantly reduced the fungal load in infectedC. 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.
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University West Lafayette, IN, USA.
Shankar
S
Thangamani
Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles Los Angeles, CA, USA.
Matthew
M
Maland
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University West Lafayette, IN, USA.
Haroon
H
Mohammad
Purdue University Libraries, Purdue UniversityWest Lafayette, IN, USA; Department of Biochemistry, Purdue UniversityWest Lafayette, IN, USA.
Pete E
PE
Pascuzzi
Bindley Bioscience Center, Purdue University West Lafayette, IN, USA.
Larisa
L
Avramova
Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California, Los Angeles Los Angeles, CA, USA.
Carla M
CM
Koehler
Bindley Bioscience Center, Purdue UniversityWest Lafayette, IN, USA; Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue UniversityWest Lafayette, IN, USA.
Tony R
TR
Hazbun
Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue UniversityWest Lafayette, IN, USA; Purdue Institute for Inflammation, Immunology, and Infectious DiseasesWest Lafayette, IN, USA.
Mohamed N
MN
Seleem
D000935:Antifungal Agents / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D058492:Drug Repositioning; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D057895:Haploinsufficiency; D006801:Humans; D008564:Membrane Potentials; D008826:Microbial Sensitivity Tests; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D017382:Reactive Oxygen Species / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D000935:Antifungal Agents; C495320:MIA40 protein, S cerevisiae; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D001310:Auranofin; D050862:Oxidoreductases Acting on Sulfur Group Donors; C073790:ERV1 protein, S cerevisiae
Mia40-Erv1 pathway; antifungal; auranofin; chemogenomic profiling; repurposing