CgPDR1 gain-of-function mutations lead to azole-resistance and increased adhesion in clinical Candida glabrata strains

Abstract

Background

Recently, Candida glabrata has emerged as a health-threatening pathogen and the rising resistance to antifungal agent in C. glabrata often leads to clinical treatment failure.

Objective

To investigate the evolution of drug resistance and adherence ability in four paired clinical isolates collected before and after antifungal treatment.

Methods

Sequence analysis, gene disruption, drug-susceptibility, adhesion tests, and real-time quantitative PCR were performed.

Results

The azole-susceptible strains acquired azole resistance after antifungal therapy. Four gain-of-function (GOF) mutations in CgPDR1 were revealed by sequence analysis, namely G1099D, G346D, L344S and P927S, the last being reported for the first time. CDR1, CDR2 and SNQ2 efflux pump gene expression levels were elevated in strains harboring GOF mutations in CgPDR1, resulting in decreased azole susceptibility. CgPDR1 alleles with distinct GOF mutations displayed different expression profiles for the drug-related genes. CgPDR1 GOF mutations led to increased efflux pumps expression levels in a strain background independent way. Hyperactive Pdr1^G1099D and Pdr1^P927S displayed strain background-dependent increased adherence to host cells via upregulation of EPA1 transcription. Interestingly, the drug transporter gene expression levels did not always correspond with that of the adhesin EPA1 gene.

Conclusions

GOF mutations in CgPDR1 conferred drug resistance and increased adherence in the clinical strains, possibly endowing C. glabrata with increased viability and pathogenicity.

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