1 Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montreal, Quebec, H4B 1R6, Canada.
2 McGill University Health Centre Research Institute and Meakins-Christie Laboratories, 1001 Boulevard Decarie West, Montreal, Quebec, H4A 3J1, Canada.
3 Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montreal, Quebec, H4B 1R6, Canada. ann.english@concordia.ca.

Ctt1 catalase activity potentiates antifungal azoles in the emerging opportunistic pathogen Saccharomyces cerevisiae.

Sci Rep. 2019 Jun 24;9(1):9185

Authors: Martins D, Nguyen D, English AM

Abstract

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 ctt1? cells, which possess negligible catalase activity, we link azole potentiation with Ctt1 upregulation. In contrast, sod2? 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 ctt1? 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.

PMID: 31235707 [PubMed - in process]