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

Kelley R. Healey, Yanan Zhao, Winder B. Perez, Shawn R. Lockhart, Jack D. Sobel, Dimitrios Farmakiotis, Dimitrios P. Kontoyiannis, Dominique Sanglard, Saad J. Taj-Aldeen, Barbara D. Alexander, Cristina Jimenez-Ortigosa, Erika Shor and David S. Perlin ()
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Kelley R. Healey: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences
Yanan Zhao: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences
Winder B. Perez: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences
Shawn R. Lockhart: Centers for Disease Control and Prevention
Jack D. Sobel: Wayne State University School of Medicine
Dimitrios Farmakiotis: The University of Texas MD Anderson Cancer Center
Dimitrios P. Kontoyiannis: The University of Texas MD Anderson Cancer Center
Dominique Sanglard: Institute of Microbiology of the University Hospital of Lausanne
Saad J. Taj-Aldeen: Hamad Medical Corporation
Barbara D. Alexander: Duke University
Cristina Jimenez-Ortigosa: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences
Erika Shor: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences
David S. Perlin: Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11128

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