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Updated: Jul 10, 2025
Whole Genome Sequencing of Candida glabrata for Detection of Markers of Antifungal Drug Resistance
Published on: December 28, 2017
Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species
Karolina M Czajka1, Krishnan Venkataraman1,2, Danielle Brabant-Kirwan3
1Medical Sciences Division, NOSM University, 935 Ramsey Lake Rd., Sudbury, ON P3E 2C6, Canada.
Abstract:
Candidiasis is a highly pervasive infection posing major health risks, especially for immunocompromised populations. Pathogenic Candida species have evolved intrinsic and acquired resistance to a variety of antifungal medications. The primary goal of this literature review is to summarize the molecular mechanisms associated with antifungal resistance in Candida species. Resistance can be conferred via gain-of-function mutations in target pathway genes or their transcriptional regulators. Therefore, an overview of the known gene mutations is presented for the following antifungals: azoles (fluconazole, voriconazole, posaconazole and itraconazole), echinocandins (caspofungin, anidulafungin and micafungin), polyenes (amphotericin B and nystatin) and 5-fluorocytosine (5-FC). The following mutation hot spots were identified: (1) ergosterol biosynthesis pathway mutations (ERG11 and UPC2), resulting in azole resistance; (2) overexpression of the efflux pumps, promoting azole resistance (transcription factor genes: tac1 and mrr1; transporter genes: CDR1, CDR2, MDR1, PDR16 and SNQ2); (3) cell wall biosynthesis mutations (FKS1, FKS2 and PDR1), conferring resistance to echinocandins; (4) mutations of nucleic acid synthesis/repair genes (FCY1, FCY2 and FUR1), resulting in 5-FC resistance; and (5) biofilm production, promoting general antifungal resistance. This review also provides a summary of standardized inhibitory breakpoints obtained from international guidelines for prominent Candida species. Notably, N. glabrata, P. kudriavzevii and C. auris demonstrate fluconazole resistance.
Insights
Antifungal resistance in Candida species is driven by gene mutations affecting drug targets and efflux pumps. Key species like Candida auris show resistance to fluconazole, highlighting urgent treatment challenges.
Area of Science:
- Medical Mycology
- Molecular Biology
- Infectious Diseases
Background:
- Candidiasis poses significant health risks, particularly for immunocompromised individuals.
- Candida species exhibit increasing resistance to antifungal drugs, complicating treatment.
- Understanding resistance mechanisms is crucial for effective therapeutic strategies.
Purpose of the Study:
- To review the molecular mechanisms of antifungal resistance in Candida species.
- To identify specific gene mutations conferring resistance to major antifungal classes.
- To summarize standardized antifungal susceptibility breakpoints for clinical guidance.
Main Methods:
- Literature review of molecular mechanisms of antifungal resistance.
- Analysis of gene mutations associated with resistance to azoles, echinocandins, polyenes, and 5-fluorocytosine.
- Compilation of international guidelines on antifungal inhibitory breakpoints.
Main Results:
- Azole resistance is linked to mutations in the ergosterol biosynthesis pathway (ERG11, UPC2) and efflux pump overexpression (CDR1, CDR2, MDR1).
- Echinocandin resistance involves cell wall biosynthesis mutations (FKS1, FKS2, PDR1).
- 5-Fluorocytosine resistance stems from mutations in nucleic acid synthesis/repair genes (FCY1, FCY2, FUR1).
- Biofilm formation contributes to general antifungal resistance.
- Specific species like Candida glabrata, Pichia kudriavzevii, and Candida auris demonstrate inherent fluconazole resistance.
Conclusions:
- Molecular mechanisms, including specific gene mutations and efflux pump activity, are key drivers of Candida antifungal resistance.
- Emerging resistance in species like C. auris necessitates updated treatment guidelines and novel therapeutic approaches.
- Standardized breakpoints are essential for accurate interpretation of antifungal susceptibility testing.
