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Candida albicans enhances iron uptake to maintain fluconazole resistance

Rishabh Sharma1, Anubhav Nahar1, Sumant Puri1

  • 1Oral Microbiome Research Laboratory, Kornberg School of Dentistry, Temple University, Philadelphia, Pennsylvania, USA.

Infection and Immunity
|February 7, 2025
PubMed

Insights

Fluconazole-resistant Candida species accumulate more iron, increasing resistance. The iron chelator deferasirox (DFX) combined with fluconazole effectively kills resistant strains, offering a new treatment strategy.

Area of Science:

  • Mycology and Antimicrobial Resistance
  • Molecular Biology and Fungal Pathogenesis
  • Pharmacology and Drug Discovery

Background:

  • Widespread fluconazole use drives the emergence of resistant Candida species, complicating clinical management.
  • Iron homeostasis is critical in fungi, influencing membrane composition and antifungal drug susceptibility.
  • Fluconazole targets ergosterol in fungal membranes, a pathway potentially modulated by iron availability.

Purpose of the Study:

  • To investigate the role of iron in fluconazole resistance in Candida albicans.
  • To evaluate the efficacy of the iron chelator deferasirox (DFX) in overcoming fluconazole resistance.
  • To explore the potential of DFX as a standalone or combination therapy against resistant fungal infections.

Main Methods:

  • Generation and characterization of a fluconazole-resistant (FR) Candida albicans strain.
  • Determination of minimum inhibitory concentrations (MICs) for fluconazole and DFX.
  • Quantification of intracellular iron levels and gene expression analysis of iron-uptake and ergosterol biosynthesis pathways.
  • In vivo studies using a murine model to assess treatment efficacy in high-iron versus low-iron conditions.

Main Results:

  • The FR strain exhibited significantly higher intracellular iron accumulation and upregulated iron-uptake genes compared to the susceptible strain.
  • FR strains showed increased ergosterol levels and enhanced expression of ergosterol biosynthesis genes, correlating with fluconazole resistance.
  • A sublethal dose of DFX synergized with fluconazole to effectively kill the FR strain, both in vitro and in vivo, particularly in high-iron environments.

Conclusions:

  • Fluconazole-resistant Candida albicans actively uptakes iron to support resistance mechanisms, including altered ergosterol biosynthesis.
  • Deferasirox demonstrates potential as an adjuvant therapy, overcoming fluconazole resistance by targeting iron accumulation.
  • Combination therapy with DFX and fluconazole offers a promising strategy to combat challenging drug-resistant fungal infections.
Keywords:
Candida albicansantifungal drug-resistancedeferasiroxergosterolfluconazoleironiron chelatororopharyngeal candidiasisβ-glucan

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