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Doxorubicin selects for fluconazole-resistant petite mutants in Candida glabrata isolates
Bettina Schulz1, Mathias Knobloch, Kai Weber
1Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Department of Oncology and Hematology, Charitéplatz 1, 10117 Berlin, Germany. bettina schulz@arcor.de
Abstract:
Candida infections are a permanent threat to immunocompromised individuals such as cancer patients, and Candida glabrata has emerged as a major problem in recent years. Resistance may develop during lengthy antifungal therapies and is often mediated by upregulation of fungal drug efflux pumps. During chemotherapy the yeast cell is also exposed to cytotoxic agents that may affect its drug susceptibility. Four C. glabrata isolates, three susceptible and one resistant to fluconazole (FLU), were incubated with 20 μg/ml of doxorubicin (DOX) for 90 min. In a second experiment, the isolates were cultured with DOX for ten days. Samples were taken on subsequent days to determine the minimal inhibitory concentration (MIC) of FLU and to analyze expression of CgCDR1, CgCDR2, CgSNQ2 and CgPDR1. Samples were also used to assess the petite phenotype. Short-term DOX exposure did not induce efflux pump gene expression, but genes were consistently overexpressed in FLU-susceptible isolates during long-term exposure. An increase in MIC values on day 6 in two of the isolates coincided with the first occurrence of petite mutants in all susceptible isolates. The respiratory deficiency of selected petite mutants was confirmed by culturing mutants on agar containing glycerol as the sole carbon source. FLU MIC values for respiratory-deficient clones were ≥64 μg/ml, and efflux pump gene expression was greatly increased. The resistant isolate did not develop mitochondrial dysfunction. In summary, the cytotoxic agent DOX selects for FLU-resistant respiratory-deficient C. glabrata mutants, which may affect antifungal therapy.
Insights
The chemotherapy drug doxorubicin (DOX) can select for fluconazole (FLU)-resistant Candida glabrata. This resistance is linked to respiratory deficiency and mitochondrial dysfunction in the yeast, potentially impacting antifungal treatment efficacy.
Area of Science:
- Mycology
- Medical Microbiology
- Antifungal Resistance
Background:
- Candida glabrata poses a significant threat to immunocompromised patients, particularly cancer patients undergoing chemotherapy.
- Antifungal resistance, often mediated by drug efflux pumps, complicates treatment during lengthy antifungal therapies.
- Chemotherapy agents may influence yeast drug susceptibility.
Purpose of the Study:
- To investigate the effect of the cytotoxic agent doxorubicin (DOX) on fluconazole (FLU) susceptibility and resistance mechanisms in Candida glabrata.
- To determine if short-term or long-term exposure to DOX induces changes in efflux pump gene expression and drug resistance.
- To assess the role of mitochondrial dysfunction and petite phenotype in DOX-induced FLU resistance.
Main Methods:
- Incubation of susceptible and resistant C. glabrata isolates with DOX for short-term (90 min) and long-term (10 days) periods.
- Determination of minimal inhibitory concentrations (MICs) for FLU.
- Analysis of CgCDR1, CgCDR2, CgSNQ2, and CgPDR1 efflux pump gene expression.
- Assessment and confirmation of the petite phenotype and respiratory deficiency.
Main Results:
- Short-term DOX exposure did not induce efflux pump gene expression.
- Long-term DOX exposure led to consistent overexpression of efflux pump genes in FLU-susceptible isolates.
- Increased FLU MICs correlated with the emergence of petite mutants exhibiting respiratory deficiency and significantly elevated efflux pump gene expression.
- The inherently resistant isolate did not develop mitochondrial dysfunction.
Conclusions:
- The cytotoxic agent DOX selects for fluconazole-resistant, respiratory-deficient Candida glabrata mutants.
- Mitochondrial dysfunction plays a crucial role in the development of DOX-induced FLU resistance in C. glabrata.
- These findings highlight a potential mechanism that could compromise antifungal therapy in cancer patients.
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