Fructose Induces Fluconazole Resistance in Candida albicans through Activation of Mdr1 and Cdr1 Transporters

Abstract

Candida albicans is a pathogenic fungus that is increasingly developing multidrug resistance (MDR), including resistance to azole drugs such as fluconazole (FLC). This is partially a result of the increased synthesis of membrane efflux transporters Cdr1p, Cdr2p, and Mdr1p. Although all these proteins can export FLC, only Cdr1p is expressed constitutively. In this study, the effect of elevated fructose, as a carbon source, on the MDR was evaluated. It was shown that fructose, elevated in the serum of diabetics, promotes FLC resistance. Using C. albicans strains with green fluorescent protein (GFP) tagged MDR transporters, it was determined that the FLC-resistance phenotype occurs as a result of Mdr1p activation and via the increased induction of higher Cdr1p levels. It was observed that fructose-grown C. albicans cells displayed a high efflux activity of both transporters as opposed to glucose-grown cells, which synthesize Cdr1p but not Mdr1p. Additionally, it was concluded that elevated fructose serum levels induce the de novo production of Mdr1p after 60 min. In combination with glucose, however, fructose induces Mdr1p production as soon as after 30 min. It is proposed that fructose may be one of the biochemical factors responsible for Mdr1p production in C. albicans cells.

Lactate Like Fluconazole Reduces Ergosterol Content in the Plasma Membrane and Synergistically Kills Candida albicans

“…Candidiasis treatment is no exception in this case, and it is important to take into consideration the effects of compounds that naturally occur in niches where C. albicans is present in the body. Recently, our research showed that fructose activates Mdr1 and Cdr1 transporters in C. albicans in response to the presence of FLC [ 18 ]. Furthermore, we demonstrated that capric acid produced by probiotic yeast Saccharomyces boulardii influences the susceptibility of C. albicans to FLC and AmB [ 23 ].…”

“…Electrophoretic separation and transfer of Cdr1p- GFP was also performed as previously described [ 42 ]. For detection, a monoclonal mouse anti- GFP primary antibody was used, followed by an HRP-conjugated rabbit anti-mouse secondary antibody [ 18 ]. The remaining steps were performed as described [ 42 ].…”

“…Suspensions of CAF2-1, in 25 mL HEPES–NaOH (A 600 = 1.0), were grown in YPD or YPL medium with 2-deoxy-D-glucose and stained with R6G as previously described [ 18 ]. In each of the conditions, the R6G uptake was estimated to be ≥95%.…”

“…The mechanism of resistance of C. albicans to FLC consists mainly in the efflux of this compound by three membrane transporters, namely, Cdr1, Cdr2, and Mdr1. It was previously found that the type of carbon source affects the resistance of C. albicans to FLC [ 18 ]. Interestingly, the expressions of both CDRS and MDR1 were decreased when the cells were grown on either glycerol or acetate compared with those grown on glucose [ 19 ].…”

Antiadhesive Properties of Imidazolium Ionic Liquids Based on (−)-Menthol Against Candida spp.

“…Prophylaxis with antifungal agents leads to the emergence of resistant strains [12,20], especially to azole antifungals [21].…”