Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance
| Autor: | David S. Perlin, Yanan Zhao, Dimitrios Farmakiotis, Shawn R. Lockhart, Dimitrios P. Kontoyiannis, Jack D. Sobel, Barbara D. Alexander, Winder B. Perez, Dominique Sanglard, Erika Shor, Saad J. Taj-Aldeen, Cristina Jiménez-Ortigosa, Kelley R. Healey |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Antifungal Antifungal Agents Genotype medicine.drug_class Science Antifungal drugs Genes Fungal 030106 microbiology Colony Count Microbial General Physics and Astronomy Candida glabrata Animals Antifungal Agents/pharmacology Antifungal Agents/therapeutic use Candida glabrata/genetics Candida glabrata/isolation & purification Candidiasis/drug therapy Candidiasis/microbiology 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 Humans Kidney/drug effects Kidney/microbiology Mice Mutation/genetics Phenotype Drug resistance Biology Kidney Article General Biochemistry Genetics and Molecular Biology Microbiology Echinocandins 03 medical and health sciences Drug Resistance Fungal medicine Gene Genetics Multidisciplinary Candidiasis General Chemistry Fungal pathogen bacterial infections and mycoses biology.organism_classification Drug Resistance Multiple 3. Good health Mutation DNA mismatch repair |
| Zdroj: | Nature Communications, vol. 7, pp. 11128 Nature Communications, Vol 7, Iss 1, Pp 1-10 (2016) Nature Communications |
| Popis: | 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. The fungal pathogen Candida glabrata readily acquires resistance to multiple types of antifungal drugs. Here, Healey et al. show that C. glabrata clinical isolates often carry mutations in a gene involved in DNA mismatch repair, and this is associated with increased propensity to develop antifungal resistance. |
| Databáze: | OpenAIRE |
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