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Identification of a Cryptococcus neoformans cytochrome P450 lanosterol 14α-demethylase (Erg11) residue critical for differential susceptibility between fluconazole/voriconazole and itraconazole/posaconazole
Year:
2012
Authors :
Sionov, Edward
;
.
Volume :
56
Co-Authors:
Sionov, E., Laboratory of Clinical Infectious Diseases, Bioinformatics and Computational Biosciences Branch, National Institutes of Health, Bethesda, MD, United States
Chang, Y.C., Laboratory of Clinical Infectious Diseases, Bioinformatics and Computational Biosciences Branch, National Institutes of Health, Bethesda, MD, United States
Garraffo, H.M., Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
Dolan, M.A., Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
Ghannoum, M.A., Center for Medical Mycology, Case Western Reserve University, Cleveland, OH, United States
Kwon-Chung, K.J., Laboratory of Clinical Infectious Diseases, Bioinformatics and Computational Biosciences Branch, National Institutes of Health, Bethesda, MD, United States
Facilitators :
From page:
1162
To page:
1169
(
Total pages:
8
)
Abstract:
Cryptococcus neoformans strains resistant to azoles due to mutations causing alterations in the ERG11 gene, encoding lanosterol 14α- demethylase, have rarely been reported. In this study, we have characterized a C. neoformans serotype A strain that is resistant to high concentrations of fluconazole (FLC). This strain, which was isolated from an FLC-treated patient, contained five missense mutations in the ERG11 gene compared to the sequence of reference strain H99. Molecular manipulations of the ERG11 gene coupled with susceptibility to triazole revealed that a single missense mutation resulting in the replacement of tyrosine by phenylalanine at amino acid 145 was sufficient to cause the high FLC resistance of the strain. Importantly, this newly identified point mutation in the ERG11 gene of C. neoformans afforded resistance to voriconazole (VRC) but increased susceptibility to itraconazole (ITC) and posaconazole (PSC), which are structurally similar to each other but distinct from FLC/VRC. The in vitro susceptibility/resistance of the strains with or without the missense mutation was reflected in the therapeutic efficacy of FLC versus ITC in the animals infected with the strains. This study shows the importance of the Y145F alteration of Erg11 in C. neoformans for manifestation of differential susceptibility toward different triazoles. It underscores the necessity of in vitro susceptibility testing for each FLC-resistant C. neoformans clinical isolate against different groups of azoles in order to assist patient management. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
Note:
Related Files :
animal experiment
animal model
Animals
Female
mice
Phenylalanine
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More details
DOI :
10.1128/AAC.05502-11
Article number:
Affiliations:
Database:
Scopus
Publication Type:
article
;
.
Language:
English
Editors' remarks:
ID:
18841
Last updated date:
02/03/2022 17:27
Creation date:
16/04/2018 23:24
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Scientific Publication
Identification of a Cryptococcus neoformans cytochrome P450 lanosterol 14α-demethylase (Erg11) residue critical for differential susceptibility between fluconazole/voriconazole and itraconazole/posaconazole
56
Sionov, E., Laboratory of Clinical Infectious Diseases, Bioinformatics and Computational Biosciences Branch, National Institutes of Health, Bethesda, MD, United States
Chang, Y.C., Laboratory of Clinical Infectious Diseases, Bioinformatics and Computational Biosciences Branch, National Institutes of Health, Bethesda, MD, United States
Garraffo, H.M., Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
Dolan, M.A., Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
Ghannoum, M.A., Center for Medical Mycology, Case Western Reserve University, Cleveland, OH, United States
Kwon-Chung, K.J., Laboratory of Clinical Infectious Diseases, Bioinformatics and Computational Biosciences Branch, National Institutes of Health, Bethesda, MD, United States
Identification of a Cryptococcus neoformans cytochrome P450 lanosterol 14α-demethylase (Erg11) residue critical for differential susceptibility between fluconazole/voriconazole and itraconazole/posaconazole
Cryptococcus neoformans strains resistant to azoles due to mutations causing alterations in the ERG11 gene, encoding lanosterol 14α- demethylase, have rarely been reported. In this study, we have characterized a C. neoformans serotype A strain that is resistant to high concentrations of fluconazole (FLC). This strain, which was isolated from an FLC-treated patient, contained five missense mutations in the ERG11 gene compared to the sequence of reference strain H99. Molecular manipulations of the ERG11 gene coupled with susceptibility to triazole revealed that a single missense mutation resulting in the replacement of tyrosine by phenylalanine at amino acid 145 was sufficient to cause the high FLC resistance of the strain. Importantly, this newly identified point mutation in the ERG11 gene of C. neoformans afforded resistance to voriconazole (VRC) but increased susceptibility to itraconazole (ITC) and posaconazole (PSC), which are structurally similar to each other but distinct from FLC/VRC. The in vitro susceptibility/resistance of the strains with or without the missense mutation was reflected in the therapeutic efficacy of FLC versus ITC in the animals infected with the strains. This study shows the importance of the Y145F alteration of Erg11 in C. neoformans for manifestation of differential susceptibility toward different triazoles. It underscores the necessity of in vitro susceptibility testing for each FLC-resistant C. neoformans clinical isolate against different groups of azoles in order to assist patient management. Copyright © 2012, American Society for Microbiology. All Rights Reserved.
Scientific Publication
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