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Updated: Jun 21, 2026
Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis
Published on: March 19, 2019
The alternative oxidase of Candida albicans causes reduced fluconazole susceptibility
Lan Yan1, Miaohai Li, Yongbing Cao
1Department of Pharmacology, College of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Objectives:
To evaluate the effect of Candida albicans mitochondrial respiratory status on antifungal azole susceptibility.
Methods:
The inhibitors cyanide and salicylhydroxamic acid (SHAM) were each combined with azoles to examine the effect of the combinations on C. albicans. C. albicans strains deleted for the alternative oxidase (Aox) were also examined for susceptibility to azoles and for the generation of intracellular reactive oxygen species (ROS). A chequerboard microdilution assay was performed on several C. albicans clinical strains including azole-resistant isolates to explore the combined effect of fluconazole and inhibitors of Aox.
Results:
The induction of the alternative respiratory pathway by cyanide decreased susceptibility to azoles, while the inhibition of alternative respiration by SHAM increased azole susceptibility. It was found that ROS production was increased in the absence of Aox in C. albicans upon treatment by antifungals such as miconazole and benomyl. The combination of fluconazole with SHAM resulted in a synergistic effect on the killing of C. albicans clinical isolates.
Conclusion:
These results demonstrate that the induction of the alternative respiratory pathway confers reduced susceptibility to antifungal azoles, potentially through a mechanism that involves decreased intracellular ROS production during exposure to antifungal agents.
Insights
Candida albicans mitochondrial respiration affects azole antifungal drug effectiveness. Activating the alternative respiratory pathway reduces susceptibility, while inhibiting it increases it, offering new therapeutic strategies.
Area of Science:
- Medical Mycology
- Antifungal Drug Resistance
- Mitochondrial Respiration
Background:
- Azole antifungals are crucial for treating Candida albicans infections.
- Understanding resistance mechanisms is vital for effective antifungal therapy.
- Mitochondrial respiration plays a role in fungal physiology and drug response.
Purpose of the Study:
- To investigate the impact of Candida albicans mitochondrial respiratory status on susceptibility to azole antifungals.
- To explore the relationship between the alternative oxidase pathway and azole resistance.
Main Methods:
- Utilized inhibitors cyanide and salicylhydroxamic acid (SHAM) in combination with azoles.
- Examined azole susceptibility and reactive oxygen species (ROS) generation in C. albicans strains lacking the alternative oxidase (Aox).
- Performed chequerboard microdilution assays with fluconazole and Aox inhibitors on clinical isolates, including azole-resistant strains.
Main Results:
- Cyanide-induced alternative respiration decreased azole susceptibility; SHAM inhibition increased it.
- Absence of Aox led to increased ROS production in C. albicans treated with miconazole and benomyl.
- Combination of fluconazole and SHAM showed synergistic killing of C. albicans clinical isolates.
Conclusions:
- Induction of the alternative respiratory pathway confers reduced susceptibility to antifungal azoles.
- This resistance may involve decreased intracellular ROS production during antifungal exposure.
- Targeting mitochondrial respiration presents a potential strategy to overcome azole resistance in C. albicans.
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