Systematic Phenotyping of a Large-Scale Candida glabrata Deletion Collection Reveals Novel Antifungal Tolerance Genes

PLoS Pathogens

Sophie Bachellier-Bassi¹  Marina Marcet-Houben²  Brian Green³  Dominique Ferrandon³  Murielle Chauvel⁴  Lauren Ames⁴  Bernhard Hube⁴  Biao Ma⁵  Vitor Cabral⁵  Katja Seider⁶  Ekkehard Hiller⁶  Ute Zeidler⁷  Arnaud Firon⁷  Jessica Quintin⁸  Walter Glaser⁸  Ingrid Frohner⁹  Ilse D. Jacobsen⁹  Karl Kuchler⁹  Ken Haynes⁹  Brendan Cormack^1,10  Steffen Rupp^1,11  Michael Tscherner^1,11  Tobias Schwarzmüller^1,11  Sascha Brunke^1,11  Christophe d'Enfert^1,11  Fabian Istel^1,12  Toni Gabaldón^1,13  Helmut Jungwirth^1,14 

[1] Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG), Barcelona, Spain;Biosciences, College of Life & Environmental Sciences, University of Exeter, Exeter, United Kingdom;Center for Sepsis Control and Care, CSCC, Jena University Hospital, Jena, Germany;Department Microbial Pathogenicity Mechanisms, Hans-Knoell-Institute, Jena, Germany;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;Friedrich Schiller University, Jena, Germany;INRA, USC2019, Paris, France;Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, Département Génomes et Génétique, Paris, France;Institut für Molekulare Biowissenschaften, Universität Graz, Graz, Austria;Medical University Vienna, Max F. Perutz Laboratories, Department of Medical Biochemistry, Vienna, Austria;Molekulare Biotechnologie MBT Fraunhofer Institut für Grenzflächen- und Bioverfahrenstechnik IGB Fraunhofer, Stuttgart, Germany;UPR 9022 du CNRS, Université de Strasbourg, Equipe Fondation Recherche Médicale, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France;Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France

关键词: Biofilms;    Cell walls;    Azoles;    Saccharomyces cerevisiae;    Antifungals;    Antimicrobial resistance;    C;    ida albicans;    Phenotypes;   

DOI  :  10.1371/journal.ppat.1004211

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY