A defect in iron uptake enhances the susceptibility of Cryptococcus neoformans to azole antifungal drugs
Open accessAbstract
The high-affinity reductive iron uptake system that includes a ferroxidase (Cfo1) and an iron permease (Cft1) is critical for the pathogenesis of Cryptococcus neoformans. In addition, a mutant lacking CFO1 or CFT1 not only has reduced iron uptake but also displays a markedly increased susceptibility to azole antifungal drugs. Altered antifungal susceptibility of the mutants was of particular interest because the iron uptake system has been proposed as an alternative target for antifungal treatment. In this study, we used transcriptome analysis to begin exploring the molecular mechanisms of altered antifungal susceptibility in a cfo1 mutant. The wild-type strain and the cfo1 mutant were cultured with or without the azole antifungal drug fluconazole and their transcriptomes were compared following sequencing with Illumina Genome Analyzer IIx (GAIIx) technology. As expected, treatment of both strains with fluconazole caused elevated expression of genes in the ergosterol biosynthetic pathway that includes the target enzyme Erg11. Additionally, genes differentially expressed in the cfo1 mutant were involved in iron uptake and homeostasis, mitochondrial functions and respiration. The cfo1 mutant also displayed phenotypes consistent with these changes including a reduced ratio of NAD(+)/NADH and down-regulation of Fe-S cluster synthesis. Moreover, combination treatment of the wild-type strain with fluconazole and the respiration inhibitor diphenyleneiodonium dramatically increased susceptibility to fluconazole. This result supports the hypothesis that down-regulation of genes required for respiration contributed to the altered fluconazole susceptibility of the cfo1 mutant. Overall, our data suggest that iron uptake and homeostasis play a key role in antifungal susceptibility and could be used as novel targets for combination treatment of cryptococcosis. Indeed, we found that iron chelation in combination with fluconazole treatment synergistically inhibited the growth of C. neoformans.
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Use of iron chelators in combination with fluconazole has been explored previously as a potential synergistic approach to treat infections caused by Candida spp. and C. neoformans.
“The use of iron chelators in combination with fluconazole has been explored previously as a potential synergistic approach to treat infections caused by pathogenic yeast such as Candida spp. (26) and C. neoformans (27).”
From <i>Candida albicans</i> enhances iron uptake to maintain fluconazole resistance (2025) · cites this paper as [27]
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<i>Candida albicans</i> enhances iron uptake to maintain fluconazole resistance
Sharma, R., Nahar, A., & Puri, S. (2025) · Infection and Immunity · doi:10.1128/iai.00002-25 · Cited by 8 · see citing works
- Authors
- Kim, J., Cho, Y.-J., Do, E., Choi, J., Hu, G., Cadieux, B., Chun, J., Lee, Y., Kronstad, J. W., & Jung, W. H.
- Affiliations
- Chung-Ang University (KR)
- Seoul National University (KR)
- University of British Columbia (CA)
- Korea Advanced Institute of Science and Technology (KR)
- Corresponding author
- Jung, Won Hee
- ORCID
- Venue
- Fungal Genetics and Biology
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 49
- Issue
- 11
- Pages
- 955-966
- ISSN
- 1087-1845 (ISSN-L)
- PMC
- PMC4706552
- OpenAlex
- W2004193133
- Cited by
- 53
- References
- 48
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 6 · 2019: 4 · 2018: 1 · 2017: 9 · 2016: 6 · 2015: 5 · 2014: 8 · 2013: 4
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Fungal Genetics and Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Ministry of Education, Science and Technology (2011-0029843, 2012-0004062)
- National Institutes of Health (R01 AI053721)
- National Research Foundation of Korea
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Cryptococcus neoformans, iron absorption, iron homeostasis, fluconazole, ergosterol biosynthesis, ERG11, respiration, mitochondrial function, NAD+/NADH ratio, diphenyleneiodonium, iron chelation, cryptococcosis, combination therapy, transcriptome
- MeSH terms
- Antifungal Agents, Azoles, Biological Transport, Ceruloplasmin, Cryptococcosis, Cryptococcus neoformans, Ergosterol, Fungal Proteins, Humans, Iron, Microbial Sensitivity Tests, Fluconazole, Gene Expression Regulation, Fungal, Gene Deletion, Drug Resistance, Fungal
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