Comparative genomic and transcriptomic analyses unveil novel features of azole resistance and adaptation to the human host in Candida glabrata

• Published in: FEMS yeast research 2018-02, Vol.18 (1), p.1
• Main Authors: Salazar, Sara Barbosa, Wang, Can, Münsterkötter, Martin, Okamoto, Michiyo, Takahashi-Nakaguchi, Azusa, Chibana, Hiroji, Lopes, Maria Manuel, Güldener, Ulrich, Butler, Geraldine, Mira, Nuno Pereira
• Format: Article
• Language: English
• Subjects: Alleles; Analysis; Anidulafungin; Antifungal Agents - pharmacology; Candida glabrata; Candida glabrata - drug effects; Candida glabrata - physiology; Candidiasis - microbiology; Carbohydrates; Caspofungin; Computational Biology - methods; Drug resistance in microorganisms; Drug Resistance, Fungal; Ethylenediaminetetraacetic acid; Fluconazole; Fluconazole - pharmacology; Gene Deletion; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Fungal; Gene Frequency; Genetic transcription; Genome, Fungal; Genomes; Genomics; Genomics - methods; Health aspects; Host-Pathogen Interactions; Humans; Molecular Sequence Annotation; Nucleotide sequence; Organic acids; Pharmaceutical industry; Physiological aspects; Sulfur; Transcription; Transcriptome; Voriconazole; Voriconazole - pharmacology; Whole genome sequencing
• ISSN: 1567-1364; 1567-1356; 1567-1364
• DOI: 10.1093/femsyr/fox079

The frequent emergence of azole resistance among Candida glabrata strains contributes to increase the incidence of infections caused by this species. Whole-genome sequencing of a fluconazole and voriconazole-resistant clinical isolate (FFUL887) and subsequent comparison with the genome of the susceptible strain CBS138 revealed prominent differences in several genes documented to promote azole resistance in C. glabrata. Among these was the transcriptional regulator CgPdr1. The CgPdr1 FFUL887 allele included a K274Q modification not documented in other azole-resistant strains. Transcriptomic profiling evidenced the upregulation of 92 documented targets of CgPdr1 in the FFUL887 strain, supporting the idea that the K274Q substitution originates a CgPdr1 gain-of-function mutant. The expression of CgPDR1K274Q in the FFUL887 background sensitised the cells against high concentrations of organic acids at a low pH (4.5), but had no detectable effect in tolerance towards other environmental stressors. Comparison of the genome of FFUL887 and CBS138 also revealed prominent differences in the sequence of adhesin-encoding genes, while comparison of the transcriptome of the two strains showed a significant remodelling of the expression of genes involved in metabolism of carbohydrates, nitrogen and sulphur in the FFUL887 strain; these responses likely reflecting adaptive responses evolved by the clinical strain during colonisation of the host.