ArticleFungal genetics and biology : FG & B2012
A defect in iron uptake enhances the susceptibility of Cryptococcus neoformans to azole antifungal drugs.
Article in Fungal genetics and biology : FG & B, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 53 citations in OpenAlex.
- Trial
- Synergic Effect of Fluconazole and Quinoline Derivatives Combination AgainstMicroorganisms · 2026Article
- Acidic pH Reduces Fluconazole Susceptibility inJournal of microbiology and biotechnology · 2025Article
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- The Interkingdom Interaction withJournal of microbiology and biotechnology · 2023Article
- Combating increased antifungal drug resistance inActa biochimica et biophysica Sinica · 2023Review
- Oxidative Stress Causes Vacuolar Fragmentation in the Human Fungal PathogenJournal of fungi (Basel, Switzerland) · 2021Article
- Review
- Iron Pathways and Iron Chelation Approaches in Viral, Microbial, and Fungal Infections.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Involvement of Mrs3/4 in Mitochondrial Iron Transport and Metabolism inJournal of microbiology and biotechnology · 2020Article
- A Transcriptional Regulatory Map of Iron Homeostasis Reveals a New Control Circuit for Capsule Formation inGenetics · 2020Article
- Multicopper Oxidases inJournal of fungi (Basel, Switzerland) · 2020Review
- Genomic Multiplication and Drug Efflux Influence Ketoconazole Resistance inFrontiers in cellular and infection microbiology · 2020Article
- Candida albicans reprioritizes metal handling during fluconazole stress.Metallomics : integrated biometal science · 2019Article
- Article
- Transcriptional Heterogeneity ofmSphere · 2018Article
- The mitochondrial ABC transporter Atm1 plays a role in iron metabolism and virulence in the human fungal pathogen Cryptococcus neoformans.Medical mycology · 2018Article
- Investigation of Cryptococcus neoformans magnesium transporters reveals important role of vacuolar magnesium transporter in regulating fungal virulence factors.MicrobiologyOpen · 2018Article
- A novel bZIP protein, Gsb1, is required for oxidative stress response, mating, and virulence in the human pathogen Cryptococcus neoformans.Scientific reports · 2017Article
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.