Digoxin Derivatives Sensitize a Saccharomyces cerevisiae Mutant Strain to Fluconazole by Inhibiting Pdr5p

Abstract

The poor outcome of treatments for fungal infections is a consequence of the increasing incidence of resistance to antifungal agents, mainly due to the overexpression of efflux pumps. To surpass this mechanism of resistance, a substance able to inhibit these pumps could be administered in association with antifungals. Saccharomyces cerevisiae possesses an efflux pump (Pdr5p) homologue to those found in pathogenic yeast. Digoxin is a natural product that inhibits Na+, K+-ATPase. The aim of this study was to evaluate whether digoxin and its derivatives (i.e., DGB, digoxin benzylidene) can inhibit Pdr5p, reversing the resistance to fluconazole in yeasts. An S. cerevisiae mutant strain that overexpresses Pdr5p was used in the assays. The effects of the compounds on yeast growth, efflux activity, and Pdr5p ATPase activity were measured. All derivatives enhanced the antifungal activity of fluconazole against S. cerevisiae, in comparison to fluconazole alone, with FICI values ranging from 0.031 to 0.500. DGB 1 and DGB 3 presented combined effects with fluconazole against a Candida albicans strain, with fractional inhibitory concentration index (FICI) values of 0.625 and 0.281, respectively The compounds also inhibited the efflux of rhodamine 6G and Pdr5p ATPase activity, with IC50 values ranging from 0.41 μM to 3.72 μM. The results suggest that digoxin derivatives impair Pdr5p activity. Considering the homology between Pdr5p and efflux pumps from pathogenic fungi, these compounds are potential candidates to be used in association with fluconazole to treat resistant fungal infections.

The Potential of Dutasteride for Treating Multidrug-Resistant Candida auris Infection

“…Even though zinc000242548690 digoxin (DR1) was rated highest in the prediction of binding affinity, it showed no anti-Candida activity, which was in line with earlier observations of C. albicans and Saccharomyces cerevisiae [51]. One hypothesis is that the cell wall or plasma membrane of C. albicans and C. auris prevented digoxin from entering the cytoplasm [51,52]. Digoxin, a cardiac glycoside, is a medication for heart conditions such as congestive heart failure and certain cardiac arrhythmias and has a narrow therapeutic window [53].…”

“…Here, the ability of C. auris to live on hospital surfaces and places other than the human body should be considered, and appropriate environmental decontamination and surface disinfection methods should be developed for hospitals and research labs to prevent the emergence of nosocomial pathogens like C. auris [ 19 , 49 , 50 ]. Even though zinc000242548690 digoxin (DR1) was rated highest in the prediction of binding affinity, it showed no anti- Candida activity, which was in line with earlier observations of C. albicans and Saccharomyces cerevisiae [ 51 ]. One hypothesis is that the cell wall or plasma membrane of C. albicans and C. auris prevented digoxin from entering the cytoplasm [ 51 , 52 ].…”

Evaluation of Systemic Antifungal Use in a Latin American General Care Hospital: A Retrospective Study

“…Regarding the presence of resistance in the fungal isolates, only the positive culture for S. cerevisiae showed resistance to fluconazole, which is part of the intrinsic resistance that yeasts have to this antifungal agent [ 30 , 31 ]. For the other 22 cultures, all species showed susceptibility to the antifungals available in the hospital, indicating a positive indication of the current resistance profile.…”