# Persistence and spread of fluconazole-resistant Candida parapsilosis clinical isolates associated with increased ERG11 copies in Qatar

## TL;DR

This study shows how fluconazole-resistant Candida parapsilosis isolates spread in hospitals in Qatar, likely due to increased ERG11 gene copies.

## Contribution

The study identifies increased ERG11 copy numbers as a novel mechanism of fluconazole resistance in C. parapsilosis clinical isolates.

## Key findings

- Fluconazole-resistant isolates had 3–7 copies of ERG11 and 2–8 copies of CDR1B, with higher gene expression.
- Genomic analysis revealed cross-hospital transmission of resistant isolates within specific genetic clusters.
- Unique mutations in EFG1 and UME6 suggest roles in biofilm formation and persistence in hospitals.

## Abstract

Candida parapsilosis is one of the most common species associated with candidemia infections globally. Recently, the emergence of fluconazole-resistant (FLU-R) C. parapsilosis has become a significant global public health concern. In this study, we investigated the genomic epidemiology and potential mechanisms of antifungal resistance among 51 hospital isolates in Qatar, of which 18 were FLU-R. Whole-genome SNP analysis revealed the presence of five major genetic clusters and evidence for cross-hospital transmission within clusters I, II and III. Cluster I had 21 isolates, including all 18 FLU-R isolates collected from 2015 to 2021. These 18 FLU-R isolates had no missense variants known to be associated with azole resistance in loci such as ERG11, ERG6 and TAC1; however, all FLU-R isolates had increased copy numbers of ERG11, ranging from 3 to 7 copies. In addition, most FLU-R isolates (n=16) had increased CDR1B copies (2–8 copies). These FLU-R isolates also had higher expression of ERG11 and CDR1B than sensitive strains. A genome-wide association study revealed 16 variants in several loci of unknown function that may be linked to resistance to FLU and 5-flucytosine. All cluster I isolates had unique missense mutations in EFG1 and UME6 that may play important roles in morphogenesis and biofilm formation. Our findings indicate these cluster I isolates may have evolved a greater propensity to persist within hospitals for prolonged periods and cause clonal transmission than isolates in other genetic clusters susceptible to fluconazole.