Isolate Specific Transcriptome Changes Exerted by Isavuconazole Treatment in Candida auris

Abstract

The sudden emergence of multidrug- and pan-resistant Candida auris isolates, combined with limited treatment options, poses significant global challenges in healthcare settings. Combination based therapies are promising alternative options to overcome C. auris related infections, where echinocandin and isavuconazole (ISA) combinations may be an interesting and promising approach. Understanding the molecular mechanisms underlying ISA treatment is crucial for developing novel therapeutic recommendations. Therefore, we investigated the gene transcription profiles of non-wild type (non-WT) and wild type (WT) C. auris isolates from the South Asian clade following ISA exposure using total RNA sequencing. The non-WT isolate was classified according to the previously reported tentative epidemiological cut-off value of ≤ 1 mg/L. ISA treatment resulted in the upregulation of 158 and 134 genes and the downregulation of 119 and 96 genes in the non-WT and WT isolates, respectively, compared with untreated samples. In general, ISA-treated isolates exhibited increased transcription of the transcriptional factor UPC2, the drug transporter MDR1, vacuolar calcium-ATPase PMC1, and several ergosterol biosynthesis genes. The WT isolate showed pronounced enrichment of genes involved in sphingolipid biosynthesis, adhesion, and drug transport. These findings suggest that alterations in membrane lipid composition and modulation of drug efflux transporters are critical processes contributing to ISA susceptibility in case of WT isolates.

Keywords: Candida auris; SCF1 gene; Ergosterol; Isavuconazole; Multidrug resistance; Transcriptome.