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bioRxiv · 10.1101/2021.08.23.457447

Transcriptional profiling of the Candida auris response to exogenous farnesol exposure

Jakab, A.·Balla, N.·Ragyak, A.·Nagy, F.·Kovacs, F.·Sajtos, Z.·Borman, A. M.·Pocsi, I.·Baranyai, E.·Majoros, L.·Kovacs, R.
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Abstract

The antifungal resistance threat posed by Candida auris necessitates bold and innovative therapeutic options. Farnesol, a quorum-sensing molecule with a potential antifungal and/or adjuvant effect; it may be a promising candidate in alternative treatment regimens. To gain further insights into the farnesol-related effect on C. auris, genome-wide gene expression analysis was performed using RNA-Seq. Farnesol exposure resulted in 1,766 differentially expressed genes. Of these, 447 and 304 genes with at least 1.5-fold increase or decrease in expression, respectively, were selected for further investigation. Genes involved in morphogenesis, biofilm events (maturation and dispersion), gluconeogenesis, iron metabolism, and regulation of RNA biosynthesis showed down-regulation, whereas those related to antioxidative defense, transmembrane transport, glyoxylate cycle, fatty acid {beta}-oxidation, and peroxisome processes were up-regulated. In addition, farnesol treatment increased the expression of certain efflux pump genes, including MDR1, CDR1, and CDR2. Growth, measured by change in CFU number, was significantly inhibited within 2 hours of the addition of farnesol (5.8x107{+/-}1.1x107 and 1.1x107{+/-}0.3x107 CFU/ml for untreated control and farnesol-exposed cells, respectively) (p<0.001). In addition, farnesol treatment caused a significant reduction in intracellular iron (152.2{+/-}21.1 vs. 116.0{+/-}10.0 mg/kg), manganese (67.9{+/-}5.1 vs. 18.6{+/-}1.8 mg/kg), and zinc (787.8{+/-}22.2 vs. 245.8{+/-}34.4 mg/kg) (p<0.05-0.001) compared to untreated control cells, whereas the level of cooper was significantly increased (274.6{+/-}15.7 vs. 828.8{+/-}106.4 mg/kg) (p<0.001). Our data demonstrate that farnesol significantly influences the growth, intracellular metal ion contents, and gene expression related to fatty acid metabolism, which could open new directions in developing alternative therapies against C. auris. ImportanceCandida auris is a dangerous fungal pathogen that causes outbreaks in health care facilities, with infections associated with high mortality rate. As conventional antifungal drugs have limited effects against the majority of clinical isolates, new and innovative therapies are urgently needed. Farnesol is a key regulator molecule of fungal morphogenesis, inducing phenotypic adaptations and influencing biofilm formation as well as virulence. Alongside these physiological modulations, it has a potent antifungal effect alone or in combination with traditional antifungals, especially at supraphysiological concentrations. However, our knowledge about the mechanisms underlying this antifungal effect against C. auris is limited. This study has demonstrated that farnesol enhances the oxidative stress and reduces the fungal survival strategies. Furthermore, it inhibits manganese, zinc transport, and iron metabolism as well as increases fungal intracellular copper content. In addition, metabolism was modulated towards {beta}-oxidation. These results provide definitive explanations for the observed antifungal effects.

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Jakab, A., Balla, N., Ragyak, A., Nagy, F., Kovacs, F., Sajtos, Z., Borman, A. M., Pocsi, I., Baranyai, E., Majoros, L., Kovacs, R.. 2021-08-26. Transcriptional profiling of the Candida auris response to exogenous farnesol exposure. https://doi.org/10.1101/2021.08.23.457447

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