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Updated: Jun 10, 2025
Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
Published on: December 28, 2017
Parallel evolution of fluconazole resistance and tolerance in Candida glabrata
Lijun Zheng1, Yi Xu2, Chen Wang2
1Department of Ultrasound Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Introduction:
With the growing population of immunocompromised individuals, opportunistic fungal pathogens pose a global health threat. Candida species, particularly C. albicans and non-albicans Candida species such as C. glabrata, are the most prevalent pathogenic fungi. Azoles, especially fluconazole, are widely used therapeutic options.
Objective:
This study investigates how C. glabrata adapts to fluconazole, with a focus on understanding the factors regulating fluconazole tolerance and its relationship to resistance.
Methods:
This study compared the factors regulating fluconazole tolerance between C. albicans and C. glabrata. We analyzed the impact of temperature on fluconazole tolerance, and requirement of calcineurin and Hsp90 for maintenance of fluconazole tolerance. We isolated colonies from edge, inside and outside of inhibition zone in disk diffusion assays. And we exposed C. glabrata strain to high concentrations of fluconazole and investigated the mutants for development of fluconazole resistance and tolerance.
Results:
We found temperature modulated tolerance in the opposite way in C. albicans strain YJB-T1891 and C. glabrata strain CG4. Calcineurin and Hsp90 were required for maintenance of fluconazole tolerance in both species. Colonies from inside and outside of inhibition zones did not exhibited mutated phenotype, but colonies isolated from edge of inhibition zone exhibited diverse phenotype changes. Moreover, we discovered that high concentrations (16-128 μg/mL) of fluconazole induce the simultaneous but parallel development of tolerance and resistance in C. glabrata, unlike the sole development of tolerance in C. albicans.
Conclusion:
This study highlights that while tolerance to fluconazole is a common response in Candida species, the specific molecular mechanisms and evolutionary pathways that lead to this response vary between species. Our findings emphasize the importance of understanding the regulation of fluconazole tolerance in different Candida species to develop effective therapeutic strategies.
Insights
This study reveals that fluconazole tolerance in Candida species is common but regulated differently. Unlike Candida albicans, Candida glabrata develops both tolerance and resistance simultaneously when exposed to high fluconazole concentrations.
Area of Science:
- Mycology
- Antimicrobial Resistance
- Molecular Biology
Background:
- Opportunistic fungal infections by Candida species are a growing concern, especially in immunocompromised individuals.
- Fluconazole is a primary antifungal treatment, but resistance and tolerance complicate therapy.
- Understanding the mechanisms of fluconazole tolerance is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the adaptation of Candida glabrata to fluconazole.
- To compare the regulation of fluconazole tolerance between Candida albicans and Candida glabrata.
- To explore the relationship between fluconazole tolerance and resistance in C. glabrata.
Main Methods:
- Comparative analysis of fluconazole tolerance factors in C. albicans and C. glabrata.
- Assessment of temperature's impact on fluconazole tolerance.
- Investigation of calcineurin and Hsp90 roles in maintaining fluconazole tolerance.
- Isolation and phenotypic analysis of Candida colonies from disk diffusion assays.
- Induction of fluconazole resistance and tolerance in C. glabrata using high drug concentrations.
Main Results:
- Temperature differentially modulated fluconazole tolerance in C. albicans and C. glabrata.
- Calcineurin and Hsp90 are essential for maintaining fluconazole tolerance in both species.
- Colonies from the edge of inhibition zones showed diverse phenotypic changes.
- High fluconazole concentrations induced simultaneous tolerance and resistance development in C. glabrata, contrasting with C. albicans.
Conclusions:
- Fluconazole tolerance mechanisms vary significantly across Candida species.
- Understanding species-specific regulation of fluconazole tolerance is vital for antifungal drug development.
- Targeting tolerance mechanisms may offer new therapeutic strategies against Candida infections.
