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Updated: Mar 25, 2026
Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis
Published on: March 19, 2019
Peroxin Pex8 couples stress responses, antifungal tolerance, and virulence regulation in Candida albicans
Bangsheng Xi1, Yongqin Wu2,3
1Department of Laboratory Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China.
Abstract:
Candida albicans, a World Health Organization critical-priority fungal pathogen, represents the predominant cause of candidemia. Therapeutic failure is sometimes driven by antifungal tolerance, a phenotype distinct from resistance, whose underlying mechanisms remain incompletely defined. Here, we identify the peroxisomal protein Pex8 as a key regulator of tolerance to both azoles and amphotericin B. Although neither deletion nor overexpression of PEX8 altered minimum inhibitory concentrations, both modifications significantly reduced drug tolerance, as demonstrated by reduced fractional growth (FoG20) and impaired survival under drug pressure. RNA-seq analysis showed that PEX8 overexpression leads to downregulation of ergosterol biosynthesis genes and remodeling of stress-response pathways, suggesting a possible transcriptional basis for the loss of azole tolerance. Complementary lipidomic profiling demonstrated that PEX8 genetic manipulations induce extensive membrane lipid remodeling, characterized by specific alterations in ceramide and lysophospholipid subclasses, thereby revealing an ergosterol-independent mechanism underlying amphotericin B tolerance attenuation. Phenotypically, PEX8 overexpression attenuated serum-induced hyphal morphogenesis and reduced virulence in a Galleria mellonella infection model, consistent with downregulation of hyphal-associated and virulence-related genes. Our findings establish Pex8 as a central coordinator of oxidative stress adaptation, membrane homeostasis, filamentation, and pathogenicity, revealing a promising target for combating antifungal tolerance.
Insights
The peroxisomal protein Pex8 regulates tolerance to antifungal drugs in Candida albicans. Modifying PEX8 impacts drug tolerance and virulence, offering a potential target for new antifungal therapies.
Area of Science:
- Mycology
- Molecular Biology
- Antimicrobial Resistance
Background:
- Candida albicans is a critical-priority fungal pathogen causing candidemia.
- Antifungal tolerance, distinct from resistance, contributes to therapeutic failure.
- Mechanisms underlying antifungal tolerance are not fully understood.
Purpose of the Study:
- To identify key regulators of antifungal tolerance in Candida albicans.
- To investigate the role of the peroxisomal protein Pex8 in antifungal tolerance.
- To explore Pex8's impact on drug tolerance, membrane homeostasis, and virulence.
Main Methods:
- Genetic manipulation of PEX8 (deletion and overexpression).
- Antifungal susceptibility testing (minimum inhibitory concentrations, fractional growth).
- RNA-sequencing (RNA-seq) for gene expression analysis.
- Lipidomic profiling for membrane lipid analysis.
- In vitro hyphal morphogenesis assays.
- Galleria mellonella infection model for virulence assessment.
Main Results:
- PEX8 genetic modifications reduced tolerance to azoles and amphotericin B without altering minimum inhibitory concentrations.
- PEX8 overexpression led to downregulation of ergosterol biosynthesis genes and altered stress-response pathways.
- PEX8 manipulation induced significant membrane lipid remodeling, affecting ceramide and lysophospholipid subclasses.
- PEX8 overexpression attenuated serum-induced hyphal morphogenesis and reduced virulence in a Galleria mellonella model.
Conclusions:
- Pex8 is a critical regulator of antifungal tolerance in Candida albicans.
- Pex8 coordinates oxidative stress adaptation, membrane homeostasis, filamentation, and pathogenicity.
- Pex8 represents a promising therapeutic target for overcoming antifungal tolerance.
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