title: Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.
abstract: The fungal pathogen Candida glabrata has emerged as a major health threat since it readily acquires resistance to multiple drug classes, including triazoles and/or echinocandins. Thus far, cellular mechanisms promoting the emergence of resistance to multiple drug classes have not been described in this organism. Here we demonstrate that a mutator phenotype caused by a mismatch repair defect is prevalent in C. glabrata clinical isolates. Strains carrying alterations in mismatch repair gene MSH2 exhibit a higher propensity to breakthrough antifungal treatment in vitro and in mouse models of colonization, and are recovered at a high rate (55% of all C. glabrata recovered) from patients. This genetic mechanism promotes the acquisition of resistance to multiple antifungals, at least partially explaining the elevated rates of triazole and multi-drug resistance associated with C. glabrata. We anticipate that identifying MSH2 defects in infecting strains may influence the management of patients on antifungal drug therapy.
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren Street, Rutgers, Newark, New Jersey 07103, USA.
authors.forename: Kelley R
authors.initials: KR
authors.lastname: Healey
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren Street, Rutgers, Newark, New Jersey 07103, USA.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren Street, Rutgers, Newark, New Jersey 07103, USA.
authors.forename: Winder B
authors.initials: WB
authors.lastname: Perez
authors.affiliation: Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop G-11, Atlanta, Georgia 30333, USA.
authors.forename: Shawn R
authors.initials: SR
authors.lastname: Lockhart
authors.affiliation: Wayne State University School of Medicine, 540 E. Canfield Avenue, 1241 Scott Hall, Detroit, Michigan 48201, USA.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Sobel
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT12.5046, Unit 1463, Houston, Texas 77030, USA.|Warren Alpert Medical School of Brown University, 593 Eddy Street, Gerry House 113, Providence, Rhode Island 02903, USA.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Farmakiotis
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT12.5046, Unit 1463, Houston, Texas 77030, USA.
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
authors.affiliation: Institute of Microbiology of the University Hospital of Lausanne, Rue Bugnon 48, CH-1011 Lausanne, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Sanglard
authors.affiliation: Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
authors.forename: Saad J
authors.initials: SJ
authors.lastname: Taj-Aldeen
authors.affiliation: Duke University, 315 Trent Drive, Hanes House, Room 163A, Durham, North Carolina 27710, USA.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Alexander
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren Street, Rutgers, Newark, New Jersey 07103, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jimenez-Ortigosa
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren Street, Rutgers, Newark, New Jersey 07103, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Shor
authors.affiliation: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren Street, Rutgers, Newark, New Jersey 07103, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Perlin
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use; D041221:Candida glabrata / Q000235:genetics* / Q000302:isolation & purification; D002177:Candidiasis / Q000188:drug therapy / Q000382:microbiology; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal / Q000187:drug effects / Q000235:genetics*; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics*; D054714:Echinocandins / Q000494:pharmacology / Q000627:therapeutic use; D017353:Gene Deletion; D005800:Genes, Fungal; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins