Abstract
Candida albicans-caused local and systemic diseases are a serious health issue worldwide, leading to high mycosis-associated morbidity and mortality. Efficient combinations of novel compounds with commonly used antifungals could be an important tool for fighting infections. The aim of this study was to evaluate the interaction of synthesized 4-(4-cyanostyryl)-1-dodecylpyridin-1-ium (CSDP+) bromide alone or in combination with fluconazole with yeast and mammalian cells. We investigated cytotoxicity of the tested agents to mammalian HEK-293 cells and the influence of CSDP+ on the ability of C. albicans wt and a clinical isolate to adhere to HEK-293. Accumulation of lipophilic cation ethidium (Et+) was used to monitor the activity of efflux pumps in HEK-293 cells. The effect of CSDP+ on the expression of the main efflux transporter genes and transcription factors in C. albicans cells as well as HEK-293 efflux pump gene ABCB1 was determined. The study showed that CSDP+ alone and in combination with fluconazole was nontoxic to HEK-293 cells and was able to reduce C. albicans adhesion. The treatment of C. albicans cells with CSDP+ in combination with fluconazole resulted in a considerable overexpression of the MDR1 and MRR1 genes. The findings suggest that these genes could be associated with efflux-related resistance to fluconazole. Measurements of Et+ fluorescence and analysis of ABCB1 gene expression demonstrated that mammalian cells were not sensitive to concentrations of CSDP+ affecting C. albicans.
Highlights
Resistance to antifungal treatment, especially to the drugs of the azole class, is a serious problem in the case of fungal pathogen Candida albicans
Our previous studies demonstrated that CSDP+ acted fungicidally against C. albicans wt, cdr1∆, cdr2∆, and cdr1∆cdr2∆ strains, and the higher concentration was required to inhibit the growth of SV1 strain cells
Our experiments demonstrated that CSDP+ at low concentrations alone or in combination with fluconazole was not toxic to HEK-293 cells
Summary
Resistance to antifungal treatment, especially to the drugs of the azole class, is a serious problem in the case of fungal pathogen Candida albicans. An important factor involved in C. albicans pathogenesis is the ability of yeasts to adhere to host cells and to change the cell shape from ellipsoidal to filamentous [3,4,5]. C. albicans adhesion to host tissues contributes to biofilm formation and increases virulence. Relatively little is known about molecular mechanisms leading to C. albicans infections in human tissues and adhesion to medicinal materials. We have demonstrated [6] that styrylpyridinium compounds, for a few decades known as fluorescent probes [7,8] or for their antimicrobial properties against bacteria [9], efficiently inhibited the growth of C. albicans cells. The most active styrylpyridinium compound 4-(4-cyanostyryl)-1-dodecylpyridin-1-ium (CSDP+ ) bromide inhibited the growth and respiration of C. albicans cells very effectively. The results of our experiments showed that in the absence
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