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. 2020 Dec 30;14(1):27.
doi: 10.3390/ph14010027.

Flavones, Flavonols, and Glycosylated Derivatives-Impact on Candida albicans Growth and Virulence, Expression of CDR1 and ERG11, Cytotoxicity

Marija Ivanov  1 , Abhilash Kannan  2 , Dejan S Stojković  1 , Jasmina Glamočlija  1 , Ricardo C Calhelha  3 , Isabel C F R Ferreira  3 , Dominique Sanglard  2 , Marina Soković  1
Affiliations

Flavones, Flavonols, and Glycosylated Derivatives-Impact on Candida albicans Growth and Virulence, Expression of CDR1 and ERG11, Cytotoxicity

Marija Ivanov et al. Pharmaceuticals (Basel). .

Abstract

Due to the high incidence of fungal infections worldwide, there is an increasing demand for the development of novel therapeutic approaches. A wide range of natural products has been extensively studied, with considerable focus on flavonoids. The antifungal capacity of selected flavones (luteolin, apigenin), flavonols (quercetin), and their glycosylated derivatives (quercitrin, isoquercitrin, rutin, and apigetrin) along with their impact on genes encoding efflux pumps (CDR1) and ergosterol biosynthesis enzyme (ERG11) has been the subject of this study. Cytotoxicity of flavonoids towards primary liver cells has also been addressed. Luteolin, quercitrin, isoquercitrin, and rutin inhibited growth of Candida albicans with the minimal inhibitory concentration of 37.5 µg/mL. The application of isoquercitrin has reduced C. albicans biofilm establishing capacities for 76%, and hyphal formation by yeast. In vitro treatment with apigenin, apigetrin, and quercitrin has downregulated CDR1. Contrary to rutin and apigenin, isoquercitrin has upregulated ERG11. Except apigetrin and quercitrin (90 µg/mL and 73 µg/mL, respectively inhibited 50% of the net cell growth), the examined flavonoids did not exhibit cytotoxicity. The reduction of both fungal virulence and expression of antifungal resistance-linked genes was the most pronounced for apigenin and apigetrin; these results indicate flavonoids' indispensable capacity for further development as part of an anticandidal therapy or prevention strategy.

Keywords: antifungal; antivirulence; biofilm; cytotoxicity; efflux pumps; flavonoids; isoquercitrin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Percentage of inhibition of C. albicans biofilm formation after treatment with MIC and subMICs (MIC/2 and MIC/4) of compounds. Values are means ± SD of three replicates.
Figure 2
Figure 2
Percentage of hyphal cells calculated by comparison with the total number of C. albicans cells. Values are means ± SD of three replicates.
Figure 3
Figure 3
Expression levels CDR1 after treatment of MIC of compounds. Fluphenazine was used as positive control. Values are expressed as Log2 fold changes (log2FC) of Relative Quantification (RQ) values, averages of two biological replicates.
Figure 4
Figure 4
Expression levels of ERG11 after treatment of MIC of compounds. Values are expressed as Log2 fold changes of RQ values, averages of two biological replicates.
See this image and copyright information in PMC

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