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Nat Commun. 2016 Mar 29;7:11128. doi: 10.1038/ncomms11128.

Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.

Author information

1
Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, 225 Warren Street, Rutgers, Newark, New Jersey 07103, USA.
2
Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop G-11, Atlanta, Georgia 30333, USA.
3
Wayne State University School of Medicine, 540 E. Canfield Avenue, 1241 Scott Hall, Detroit, Michigan 48201, USA.
4
The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, FCT12.5046, Unit 1463, Houston, Texas 77030, USA.
5
Warren Alpert Medical School of Brown University, 593 Eddy Street, Gerry House 113, Providence, Rhode Island 02903, USA.
6
Institute of Microbiology of the University Hospital of Lausanne, Rue Bugnon 48, CH-1011 Lausanne, Switzerland.
7
Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
8
Duke University, 315 Trent Drive, Hanes House, Room 163A, Durham, North Carolina 27710, USA.

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.

PMID:
27020939
PMCID:
PMC5603725
DOI:
10.1038/ncomms11128
[Indexed for MEDLINE]
Free PMC Article

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