title: Fluconazole affects the alkali-metal-cation homeostasis and susceptibility to cationic toxic compounds of Candida glabrata.
abstract: Candida glabrata is a salt-tolerant and fluconazole (FLC)-resistant yeast species. Here, we analyse the contribution of plasma-membrane alkali-metal-cation exporters, a cation/proton antiporter and a cation ATPase to cation homeostasis and the maintenance of membrane potential (ΔΨ). Using a series of single and double mutants lacking CNH1 and/or ENA1 genes we show that the inability to export potassium and toxic alkali-metal cations leads to a slight hyperpolarization of the plasma membrane of C. glabrata cells; this hyperpolarization drives more cations into the cells and affects cation homeostasis. Surprisingly, a much higher hyperpolarization of C. glabrata plasma membrane was produced by incubating cells with subinhibitory concentrations of FLC. FLC treatment resulted in a substantially increased sensitivity of cells to various cationic drugs and toxic cations that are driven into the cell by negative-inside plasma-membrane potential. The effect of the combination of FLC plus cationic drug treatment was enhanced by the malfunction of alkali-metal-cation transporters that contribute to the regulation of membrane potential and cation homeostasis. In summary, we show that the combination of subinhibitory concentrations of FLC and cationic drugs strongly affects the growth of C. glabrata cells.
authors.affiliation: Department of Membrane Transport, Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Elicharova
authors.affiliation: Department of Membrane Transport, Institute of Physiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, 142 20 Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Sychrova
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D041221:Candida glabrata / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D002412:Cations / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015725:Fluconazole / Q000494:pharmacology*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D008672:Metals, Alkali / Q000378:metabolism* / Q000633:toxicity; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; C435129:CNH1 protein, Candida albicans; D002412:Cations; D005656:Fungal Proteins; D008672:Metals, Alkali; D017923:Sodium-Hydrogen Exchangers; D015725:Fluconazole; D000254:Sodium-Potassium-Exchanging ATPase