Activity of base analogues (5-fluorouracil, 5-flucytosine) against planktonic cells and mature biofilm of Candida yeast. Effect of combination with folinic acid

Abstract

BackgroundThe increasing number of Candida infections, especially those caused by non-C. albicans species and resistant strains, is a serious medical problem. ObjectivesIn this study, the antifungal activity of base analogues, 5-flucytosine (5-FC) and 5-fluorouracil (5-FU), was tested against planktonic cells as well as against mature biofilm. MethodsTests were performed according the EUCAST methodology. Antibiofilm effectiveness of tested drugs was determined by the crystal violet staining method. The cytotoxicity assays was performed according to the ISO 10993-5 norm. Results5-FC and 5-FU were effective against fifteen fluconazole resistant Candida glabrata strains with an average minimal inhibitory concentration (MIC) of 0.152mg/L and 0.39mg/L, respectively. Folinic acid (folinate- e.g., leucovorin) is a common drug used in oncology simultaneously with 5-FU. In our tests folinate was able to lower MIC for 5-FC from 0.152 to 0.058mg/L (P<0.05). In the biofilm assay 5-FU and 5-FC alone did not induce any changes in the biomass of mature biofilm. Addition of folinate to each base analogue resulted in up to 90% reduction of biomass. Viability tests show that a concentration of 64mg/L of 5-FC and 5-FU supplemented with folinate can be fungicidal against mature biofilms of some Candida isolates. No cytotoxic effect was found for combination of FOL and 5-FC. ConclusionTherapy of 5-FU+folinate is well known in cancer treatment, in this study we reveal the beneficial effect of folinate on antifungal activity of 5-FC as well as the antifungal potential of 5-FU+folinate.