Cited by 31Antifungal resistance and susceptibilityFungal and yeast genetics researchYeasts and Rust Fungi Studies

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

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Salazar, Sara Barbosa, Wang, Can, Münsterkötter, Martin, Okamoto, Michiyo, Takahashi-Nakaguchi, Azusa, Chibana, Hiroji, Lopes, Maria Manuel, Güldener, Ulrich +2 more·2018·FEMS Yeast Research

Abstract

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.

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Crossref · 10.1093/femsyr/fox079

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  • At least 78 genes have been suggested to be implicated in C. glabrata resistance to fluconazole and voriconazole.

    “However, there may still be alternative routes to the acquisition of resistance in C. glabrata, as there have been at least 78 genes suggested to be implicated in C. glabrata resistance to fluconazole and voriconazole [104].”

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Authors
Salazar, S. B., Wang, C., Münsterkötter, M., Okamoto, M., Takahashi-Nakaguchi, A., Chibana, H., Lopes, M. M., Güldener, U., Butler, G., & Mira, N. P.
Affiliations
  • University of Lisbon (PT)
  • University College Dublin (IE)
  • Helmholtz Munich (DE)
  • Chiba University (JP)
Corresponding author
Mira, Nuno Pereira
Venue
FEMS Yeast Research
Published
2017-10-26
Volume
18
Issue
1
ISSN
  • 1567-1356 (ISSN-L)
  • 1567-1364
OpenAlex
W2765511622
Cited by
31
References
39
Citations by year
2026: 2 · 2025: 2 · 2024: 2 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 11 · 2018: 7
FWCI
4.42
Type
journal article
Language
en
Open access
Locations
  • FEMS Yeast Research (publishedVersion)
  • PubMed (publishedVersion)
  • Site cant be reached (submittedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
Funders
FCT-Portuguese Foundation Science Foundation Ireland (UID/BIO/04565/2013, 12IA1343)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Yeasts and Rust Fungi Studies
Keywords
Candida glabrata, azole resistance, fluconazole resistance, voriconazole resistance, gain-of-function mutations, transcriptional regulation, organic acid tolerance, adhesin genes, host adaptation, clinical isolates, carbohydrate metabolism, nitrogen metabolism, sulfur metabolism
MeSH terms
Alleles, Antifungal Agents, Candidiasis, Gene Frequency, Humans, Fluconazole, Gene Expression Regulation, Fungal, Genome, Fungal, Gene Deletion, Computational Biology, Gene Expression Profiling, Genomics, Drug Resistance, Fungal, Candida glabrata, Host-Pathogen Interactions, Molecular Sequence Annotation, Transcriptome, Voriconazole

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