FKS1/2-variant independent mechanisms underlying the emergence of resistance in echinocandin-refractory Candida auris infections
4 affiliations
- 1MRC Center for Medical Mycology at the University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, United Kingdom, EX4 4QD, UK. [email protected].
- 2MRC Center for Medical Mycology at the University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, United Kingdom, EX4 4QD, UK.
- 3Institute of Infection & Immunity, St George's School of Health and Medical Sciences, City St George's University London, United Kingdom, SW17 0RE, UK.
- 4King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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 μg/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 β−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 remodelling, paving the way for resistance emergence.
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BibTeX
@article{gifford2026fks12variant,
title = {{FKS1/2-variant independent mechanisms underlying the emergence of resistance in echinocandin-refractory Candida auris infections}},
author = {Hugh Gifford and Arnab Pradhan and Ben Caswall and Sarah E Murphy and Ian Leaves and Matt B Edmondson and Tanmoy Chakraborty and Duncan Wilson and Surabhi K Taori and Neil A R Gow and Rhys A Farrer and Alistair J P Brown and Tihana Bicanic},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-76954-x},
url = {https://www.nature.com/articles/s41467-026-76954-x},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - FKS1/2-variant independent mechanisms underlying the emergence of resistance in echinocandin-refractory Candida auris infections
AU - Hugh Gifford
AU - Arnab Pradhan
AU - Ben Caswall
AU - Sarah E Murphy
AU - Ian Leaves
AU - Matt B Edmondson
AU - Tanmoy Chakraborty
AU - Duncan Wilson
AU - Surabhi K Taori
AU - Neil A R Gow
AU - Rhys A Farrer
AU - Alistair J P Brown
AU - Tihana Bicanic
PY - 2026
DA - 2026/10/15
JO - Nature Communications
DO - 10.1038/s41467-026-76954-x
UR - https://www.nature.com/articles/s41467-026-76954-x
AB - 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 μg/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 β−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 remodelling, paving the way for resistance emergence.
SN - 2041-1723
ER -