Synergistic Interactions Between Beta-Lapachone And Fluconazole In The Inhibition Of Cacdr2p And Camdr1p In Candida Albicans

Background: Mortality rate of invasive Candida infections is raising mainly amongst immunocompromised patients. These infections are hard-to-treat mainly due to the increasing incidence of resistance. The overexpression of ATP-binding cassette and major facilitator superfamily transporters is the main responsible for the failure of antifungal therapies. In a Saccharomyces cerevisiae model, beta-lapachone inhibited Pdr5p, a transporter homologous to those found in Candida albicans.Aims: To determine whether beta-lapachone reverses the resistance phenotype mediated by efflux transporters in C. albicans clinical isolates.Methods: The antifungal activity of beta-lapachone combined with fluconazole was measured by agarose chemosensitization and microdilution assays. CaCdr2p and CaMdrlp activities were evaluated through fluorescent dyes accumulation. ATPase activity was assessed using transporter-enriched plasma membranes.Results: beta-lapachone reverted antifungal resistance of S. cerevisiae and C. albicans strains overexpressing CaCdr2p and CaMdrlp transporters by inhibiting these proteins activities. CaCdr2p ATPase activity was not impaired by the compound.Conclusions: beta-lapachone is a promising drug candidate to be used as an adjuvant in the treatment of candidiasis caused by fluconazole-resistant C. albicans strains. (C) 2020 Asociacion Espanola de Micologia. Published by Elsevier Espana, S.L.U. All rights reserved.