YEAST 2017

28th International Conference on Yeast Genetics and Molecular Biology (ICYGMB)

August 27 – September 1, 2017
Prague, Czech Republic


Paper ID: 34

Comparative Genomic and Transcriptomic Analyses Unveil Novel Features of Azole Resistance and Adaptation to the Human Host in Candida glabrata

Salazar Sara1, Wang Can2, Musterkotter Martin3, Okamoto Michiyo4, Takahashi-Nakaguchi Azusa4, Chibana Hiroji4, Lopes Maria5, Güldener Ulrich6, Butler Geraldine2, Mira Nuno1, Pedreira Tiago1, Henriques Rui7

1 iBB, Institute for Bioengineering and Biosciences, Instituto superior Técnico - Department of Bioengineering, Universidade de Lisboa (Portugal)
2 School of Biomolecular and Biomedical Sciences, Conway Institute, University College of Dublin, Belfield (Ireland)
3 Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health (Germany)
4 Medical Mycology Research Center, Chiba University (Japan)
5 Faculdade de Farmácia da Universidade de Lisboa, Departamento de Microbiologa e Imunologia (Portugal)
6 Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health; Chair of Genome-oriented Bioinformatics, TUM School of Life Sciences Weihenstephan, Technical University of Munich (Germany)
7 INESC-ID and Instituto Superior Técnico, Universidade de Lisboa (Portugal)

ABSTRACT

The emergence of azole resistance among Candida glabrata strains is frequent and contributes to increase the incidence of infections caused by this species. In this work we aimed at elucidating the molecular mechanisms underlying resistance to fluconazole and voriconazole in a resistant clinical isolate (FFUL887). Whole-genome sequencing of FFUL887 and subsequent comparison with the genome of the susceptible reference strain CBS138 revealed the existence of prominent differences in several genes documented to promote azole resistance in C. glabrata. Among these was the transcriptional regulator CgPdr1. The CgPdr1 allele encoded by the FFUL887 strain included a K274Q modification not documented in other azole-resistant strains. The significant increase in susceptibility to azoles of the FFUL887 strain upon deletion of the CgPDR1K274Q allele, along with results from transcriptomic profiling rendering evident the upregulation of 80 documented targets of CgPdr1 in the FFUL887 strain, support the idea that K274Q is a novel CgPdr1 gain-of-function mutation. Analysis of the non-coding genome of the FFUL887 and of CBS138 support the idea that in the FFUL887 strain alterations of the CgPdr1-controlled regulatory network may have changed its architecture to improve the expression of azole-resistance genes. Comparison of the genome of the FFUL887 and CBS138 also showed 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 probably reflecting adaptive responses evolved by the clinical strain during colonization of the host.

Keywords:
antifungal resistance, comparative genomics and comparative transcriptomics, CgPdr1 transcription factor, Candida glabrata, fungal infections
Presented as:
  Poster [PS13-2] in PS13 Medically relevant yeasts and host microbe interactions
  Oral presentation [S9-3] in S9 Yeast pathogens and host interaction

Institute of Microbiology

YEAST 2017
28th International Conference on Yeast Genetics and Molecular Biology (ICYGMB)

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