title: Glutathione metabolism in Candida albicans resistant strains to fluconazole and micafungin.
abstract: Currently available therapies for candidiasis are based on antifungal drugs belonging to azole and echinocandin families that interfere with different aspects of fungal metabolism. These drugs, beyond their specific effects, elicit also a cellular stress including an unbalance of redox state that is counteracted not only utilizing antioxidant species but also increasing the outcome export by transporters to detoxify the internal environment. These cellular actions are both based on the cytosolic concentration of reduced glutathione (GSH). In this paper we investigated the effects of two antifungal drugs fluconazole and micafungin on the redox state of the cell in C. albicans to understand if the resistance to these drugs is accompanied by variation of glutathione metabolism. Analyses of resistant strains showed a marked difference in glutathione contents in strains resistant to fluconazole (CO23RFLC) or micafungin (CO23RFK). In CO23RFLC, the total amount of glutathione was more than doubled with respect to CO23RFK thanks to the increased activity of γ-glutamilcysteine synthetase, the key enzyme involved in GSH synthesis. We demonstrated that the GSH increase in CO23RFLC conferred to this strain a clear advantage in counteracting oxidative toxic agents while assignment of other roles, such as a more efficient elimination of the drug from the cell, should be considered more speculative. As far as MCFG resistance is concerned, from our data a role of glutathione metabolism in supporting this condition is not evident. Overall our data indicate that glutathione metabolism is differently affected in the two resistant strains and that glutathione system may play an important role in the global organization of C.albicans cells for resistance to fluconazole. Such scenario may pave the way to hypothesize the use of oxidant drugs or inhibitors able to deplete reduced glutathione level as a novel approach, for counteracting the resistance to this specific antifungal drug.
authors.affiliation: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maras
authors.affiliation: Dipartimento di Sanità Pubblica e Malattie Infettive, Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza Università di Roma, Rome, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Angiolella
authors.affiliation: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Rome, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Mignogna
authors.affiliation: Dipartimento di Sanità Pubblica e Malattie Infettive, Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza Università di Roma, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Vavala
authors.affiliation: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Macone
authors.affiliation: Dipartimento di Tecnologie e Salute, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Colone
authors.affiliation: Dipartimento di Biologia di Base ed Applicata, Università degli Studi L'Aquila, L'Aquila, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Pitari
authors.affiliation: Dipartimento di Tecnologie e Salute, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Stringaro
authors.affiliation: Dipartimento di Scienze Biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Rome, Italy.
authors.forename: Silvestro
authors.initials: S
authors.lastname: Dupré
authors.affiliation: Dipartimento di Sanità Pubblica e Malattie Infettive, Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza Università di Roma, Rome, Italy.
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Palamara
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism*; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D025141:Drug Resistance, Fungal / Q000502:physiology*; D054714:Echinocandins / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D055666:Lipopeptides / Q000494:pharmacology*; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D010084:Oxidation-Reduction
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D015725:Fluconazole; D005978:Glutathione; D000077551:Micafungin