In vitro and in vivo Effect of Exogenous Farnesol Exposure Against Candida auris

Abstract

The spreading of multidrug-resistant <i>Candida auris</i> is considered as an emerging global health threat. The number of effective therapeutic regimens is strongly limited; therefore, development of novel strategies is needed. Farnesol is a quorum-sensing molecule with a potential antifungal and/or adjuvant effect; it may be a promising candidate in alternative treatment against <i>Candida</i> species including <i>C. auris</i>. To examine the effect of farnesol on <i>C. auris</i>, we performed experiments focusing on growth, biofilm production ability, production of enzymes related to oxidative stress, triazole susceptibility and virulence. Concentrations ranging from 100 to 300 μM farnesol caused a significant growth inhibition against <i>C. auris</i> planktonic cells for 24 h (<i>p</i> < 0.01-0.05). Farnesol treatment showed a concentration dependent inhibition in terms of biofilm forming ability of <i>C. auris</i>; however, it did not inhibit significantly the biofilm development at 24 h. Nevertheless, the metabolic activity of adhered farnesol pre-exposed cells (75 μM) was significantly diminished at 24 h depending on farnesol treatment during biofilm formation (<i>p</i> < 0.001-0.05). Moreover, 300 μM farnesol exerted a marked decrease in metabolic activity against one-day-old biofilms between 2 and 24 h (<i>p</i> < 0.001). Farnesol increased the production of reactive species remarkably, as revealed by 2',7'-dichlorofluorescein (DCF) assay {3.96 ± 0.89 [nmol DCF (OD₆₄₀)^-1] and 23.54 ± 4.51 [nmol DCF (OD₆₄₀)^-1] for untreated cells and farnesol exposed cells, respectively; <i>p</i> < 0.001}. This was in line with increased superoxide dismutase level {85.69 ± 5.42 [munit (mg protein)^-1] and 170.11 ± 17.37 [munit (mg protein)^-1] for untreated cells and farnesol exposed cells, respectively; <i>p</i> < 0.001}, but the catalase level remained statistically comparable between treated and untreated cells (<i>p</i> > 0.05). Concerning virulence-related enzymes, exposure to 75 μM farnesol did not influence phospholipase or aspartic proteinase activity (<i>p</i> > 0.05). The interaction between fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole and farnesol showed clear synergism (FICI ranges from 0.038 to 0.375) against one-day-old biofilms. Regarding <i>in vivo</i> experiments, daily 75 μM farnesol treatment decreased the fungal burden in an immunocompromised murine model of disseminated candidiasis, especially in case of inocula pre-exposed to farnesol (<i>p</i> < 0.01). In summary, farnesol shows a promising therapeutic or adjuvant potential in traditional or alternative therapies such as catheter lock therapy.