Ctt1 catalase activity potentiates antifungal azoles in the emerging opportunistic pathogen Saccharomyces cerevisiae
| Autor: | Dorival Martins, Ann M. English, Dao Nguyen |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Azoles Fungal infection Antifungal Agents Saccharomyces cerevisiae Proteins Itraconazole SOD2 lcsh:Medicine Drug development Saccharomyces cerevisiae Pharmacology Article Superoxide dismutase 03 medical and health sciences Gene Knockout Techniques Stress signalling 0302 clinical medicine Drug Resistance Fungal Gene Expression Regulation Fungal Metalloproteins medicine lcsh:Science chemistry.chemical_classification Multidisciplinary biology Chemistry Clotrimazole Superoxide Dismutase lcsh:R Hydrogen Peroxide Antimicrobial responses Catalase 030104 developmental biology biology.protein Azole lcsh:Q Miconazole 030217 neurology & neurosurgery Fluconazole medicine.drug |
| Zdroj: | Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-10 (2019) |
| ISSN: | 2045-2322 |
| Popis: | Fungi respond to antifungal drugs by increasing their antioxidant stress response. How this impacts antifungal efficacy remains controversial and not well understood. Here we examine the role of catalase activity in the resistance of Saccharomyces cerevisiae to the common antifungals, fluconazole and miconazole, for which we report minimum inhibitory concentrations (MICs) of 104 and 19 μM, respectively. At sub-MIC concentrations, fluconazole and miconazole stimulate catalase activity 2-3-fold but, unexpectedly, deletion of cytosolic catalase (ctt1) makes cells more resistant to these azoles and to clotrimazole, itraconazole and posaconazole. On the other hand, upregulating Ctt1 activity by preconditioning with 0.2 mM H2O2 potentiates miconazole 32-fold and fluconazole 4-fold. Since H2O2 preconditioning does not alter the resistance of ctt1Δ cells, which possess negligible catalase activity, we link azole potentiation with Ctt1 upregulation. In contrast, sod2Δ cells deleted for mitochondrial superoxide dismutase are 4–8-fold more azole sensitive than wild-type cells, revealing that Sod2 activity protects cells against azole toxicity. In fact, the ctt1Δ mutant has double the Sod2 activity of wild-type cells so ctt1 deletion increases azole resistance in part by Sod2 upregulation. Notably, deletion of peroxisomal/mitochondrial cta1 or cytosolic sod1 does not alter fluconazole or miconazole potency. |
| Databáze: | OpenAIRE |
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