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

• Published in: Nature communications Vol. 7; no. 1; p. 11128
• Main Authors: Healey, Kelley R, Zhao, Yanan, Perez, Winder B, Lockhart, Shawn R, Sobel, Jack D, Farmakiotis, Dimitrios, Kontoyiannis, Dimitrios P, Sanglard, Dominique, Taj-Aldeen, Saad J, Alexander, Barbara D, Jimenez-Ortigosa, Cristina, Shor, Erika, Perlin, David S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 29.03.2016; Nature Portfolio
• Subjects: Animals; Antifungal Agents - pharmacology; Antifungal Agents - therapeutic use; Candida glabrata - genetics; Candida glabrata - isolation & purification; Candidiasis - drug therapy; Candidiasis - microbiology; Colony Count, Microbial; Disease Models, Animal; Drug Resistance, Fungal - drug effects; Drug Resistance, Fungal - genetics; Drug Resistance, Multiple - drug effects; Drug Resistance, Multiple - genetics; Echinocandins - pharmacology; Echinocandins - therapeutic use; Gene Deletion; Genes, Fungal; Genotype; Humans; Kidney - drug effects; Kidney - microbiology; Kidney - pathology; Mice; Mutation - genetics; Phenotype
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11128

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.