Cited by 91Antifungal resistance and susceptibilityFungal and yeast genetics researchFungal Plant Pathogen Control

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

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Thangamani, Shankar, Maland, Matthew, Mohammad, Haroon, Pascuzzi, Pete E., Avramova, Larisa, Koehler, Carla M., Hazbun, Tony R., Seleem, Mohamed N.·2017·Frontiers in Cellular and Infection Microbiology

Abstract

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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Crossref · 10.3389/fcimb.2017.00004

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  • The time required to develop and register new antifungal drugs falls short of meeting current demands.

    “However, the time required to develop and register new drugs falls short of meeting current demands [15].”

    From Statins as Antifungal Agents: A Review on Drug Repurposing and Nanotechnology-Driven Delivery Strategies (2025) · cites this paper as [15]

    The Introduction says development of new antifungals cannot keep pace with urgent demand for safe and effective drugs. It does not address the time required to register them, so that part of the claim is unsupported. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • The conventional pathway for novel drug discovery, development, and regulatory approval can span approximately 15 years, rendering it inadequate to address immediate clinical demands posed by resistant Candida infections.

    “Yet, the conventional pathway for novel drug discovery, development, and regulatory approval can span approximately 15 years, rendering it inadequate to address the immediate and growing clinical demands posed by resistant Candida infections [14, 15].”

    From Statins as Antifungal Agents: A Review on Drug Repurposing and Nanotechnology-Driven Delivery Strategies (2025) · cites this paper as [15]

    The Introduction (page not specified) says that development of new antifungals cannot keep pace with the urgent demand for safe and effective drugs, supporting the claim of unmet clinical need. It does not give an approximately 15-year timeline for drug discovery, development, and regulatory approval. (LLM, conf=0.88)

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Authors
Thangamani, S., Maland, M., Mohammad, H., Pascuzzi, P. E., Avramova, L., Koehler, C. M., Hazbun, T. R., & Seleem, M. N.
Affiliations
  • Purdue University West Lafayette (US)
  • University of California, Los Angeles (US)
Corresponding author
  • Hazbun, Tony R.
  • Seleem, Mohamed N.
Venue
Frontiers in Cellular and Infection Microbiology
Published
2017-01-18
Volume
7
Pages
4-4
ISSN
2235-2988 (ISSN-L)
OpenAlex
W2575466306
Cited by
90
References
67
Citations by year
2026: 4 · 2025: 10 · 2024: 6 · 2023: 9 · 2022: 9 · 2021: 7 · 2020: 16 · 2019: 18 · 2018: 10 · 2017: 1
FWCI
9.68
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cellular and Infection Microbiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • VTechWorks (Virginia Tech) (submittedVersion, cc-by)
  • Purdue e-Pubs (Purdue University System) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
National Institute of Allergy and Infectious Diseases (GM61721, R56AI114861)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
Keywords
auranofin, drug repurposing, antifungal activity, mitochondrial protein import, Candida biofilms, Cryptococcus neoformans, invasive fungal infections, chemogenomic profiling, Caenorhabditis elegans infection model
MeSH terms
Mitochondrial Precursor Protein Import Complex Proteins, Antifungal Agents, Auranofin, Humans, Membrane Potentials, Microbial Sensitivity Tests, Mitochondria, Oxygen Consumption, Signal Transduction, Gene Expression Regulation, Fungal, Gene Deletion, Reactive Oxygen Species, Biofilms, Gene Expression Profiling, Mitochondrial Proteins, Saccharomyces cerevisiae Proteins, Mitochondrial Membrane Transport Proteins, Oxidoreductases Acting on Sulfur Group Donors, Haploinsufficiency, Drug Repositioning

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