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PLoS Pathog. 2014 Jun 19;10(6):e1004211. doi: 10.1371/journal.ppat.1004211. eCollection 2014 Jun.

Systematic phenotyping of a large-scale Candida glabrata deletion collection reveals novel antifungal tolerance genes.

Author information

1
Medical University Vienna, Max F. Perutz Laboratories, Department of Medical Biochemistry, Vienna, Austria.
2
Department of Microbiology, Imperial College London, London, United Kingdom; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
3
Molekulare Biotechnologie MBT Fraunhofer Institut für Grenzflächen- und Bioverfahrenstechnik IGB Fraunhofer, Stuttgart, Germany.
4
Department Microbial Pathogenicity Mechanisms, Hans-Knoell-Institute, Jena, Germany; Friedrich Schiller University, Jena, Germany; Center for Sepsis Control and Care, CSCC, Jena University Hospital, Jena, Germany.
5
Department of Microbiology, Imperial College London, London, United Kingdom; Biosciences, College of Life & Environmental Sciences, University of Exeter, Exeter, United Kingdom.
6
Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Génomes et Génétique, Paris, France; INRA, USC2019, Paris, France.
7
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
8
Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Génomes et Génétique, Paris, France; INRA, USC2019, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France.
9
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona, Spain.
10
UPR 9022 du CNRS, Université de Strasbourg, Equipe Fondation Recherche Médicale, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
11
Department Microbial Pathogenicity Mechanisms, Hans-Knoell-Institute, Jena, Germany.
12
Institut für Molekulare Biowissenschaften, Universität Graz, Graz, Austria.
13
Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Génomes et Génétique, Paris, France.
14
Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.

Abstract

The opportunistic fungal pathogen Candida glabrata is a frequent cause of candidiasis, causing infections ranging from superficial to life-threatening disseminated disease. The inherent tolerance of C. glabrata to azole drugs makes this pathogen a serious clinical threat. To identify novel genes implicated in antifungal drug tolerance, we have constructed a large-scale C. glabrata deletion library consisting of 619 unique, individually bar-coded mutant strains, each lacking one specific gene, all together representing almost 12% of the genome. Functional analysis of this library in a series of phenotypic and fitness assays identified numerous genes required for growth of C. glabrata under normal or specific stress conditions, as well as a number of novel genes involved in tolerance to clinically important antifungal drugs such as azoles and echinocandins. We identified 38 deletion strains displaying strongly increased susceptibility to caspofungin, 28 of which encoding proteins that have not previously been linked to echinocandin tolerance. Our results demonstrate the potential of the C. glabrata mutant collection as a valuable resource in functional genomics studies of this important fungal pathogen of humans, and to facilitate the identification of putative novel antifungal drug target and virulence genes.

PMID:
24945925
PMCID:
PMC4063973
DOI:
10.1371/journal.ppat.1004211
[Indexed for MEDLINE]
Free PMC Article

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