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bioRxiv · 10.64898/2026.01.17.700071

FKS1/2-variant independent mechanisms underlying the emergence of resistance in echinocandin-refractory Candida auris infections

Gifford, H.·Pradhan, A.·Caswall, B.·Murphy, S.·Leaves, I.·Edmondson, M.·Chakraborty, T.·Wilson, D.·Taori, S. K.·Gow, N. A. R.·Farrer, R. A.·Brown, A. J. P.·Bicanic, T.
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Abstract

The emerging fungus Candida auris is a drug resistant global public health threat and WHO critical priority pathogen. Recommended first-line invasive candidiasis treatment is echinocandin monotherapy, but C. auris can develop on-treatment resistance via FKS1/2 gene mutations and additional, previously unexplained mechanisms. To better understand echinocandin failure in C. auris, we sequenced the genomes of echinocandin refractory FKS1/2 wild-type C. auris serial isolates from two critically unwell patients in London, UK. Population analysis profiling revealed echinocandin heteroresistance, and in vitro culture of clinical isolates at supra-MIC concentrations of anidulafungin (8 g/ml) exhibited morphotypic heterogeneity. Small colony variants (SCVs) and large colony variants (LCVs) showed elevated MICs with polyploidy (to 4n and above) alongside adaptive changes in cell wall {beta}-1,3-glucan content. LCVs contained significantly more mutations in calcineurin-related stress tolerance pathway gene CRZ1 compared to clinical parents and SCVs, associated with further increases in MIC. These findings indicate progressive step-wise accrual of adaptation to echinocandins, including genomic instability, alterations in stress tolerance pathways, and cell wall remodeling, paving the way for resistance emergence. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/700071v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@14460b7org.highwire.dtl.DTLVardef@29a598org.highwire.dtl.DTLVardef@36d187org.highwire.dtl.DTLVardef@f62c8b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Gifford, H., Pradhan, A., Caswall, B., Murphy, S., Leaves, I., Edmondson, M., Chakraborty, T., Wilson, D., Taori, S. K., Gow, N. A. R., Farrer, R. A., Brown, A. J. P., Bicanic, T.. 2026-01-18. FKS1/2-variant independent mechanisms underlying the emergence of resistance in echinocandin-refractory Candida auris infections. https://doi.org/10.64898/2026.01.17.700071

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