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

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.