Amino acid substitution in Trichophyton rubrum squalene epoxidase associated with resistance to terbinafine

Détails

ID Serval
serval:BIB_D158ADC4F811
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Amino acid substitution in Trichophyton rubrum squalene epoxidase associated with resistance to terbinafine
Périodique
Antimicrobial Agents and Chemotherapy
Auteur⸱e⸱s
Osborne  C. S., Leitner  I., Favre  B., Ryder  N. S.
ISSN
0066-4804 (Print)
Statut éditorial
Publié
Date de publication
07/2005
Volume
49
Numéro
7
Pages
2840-4
Notes
Journal Article --- Old month value: Jul
Résumé
There has only been one clinically confirmed case of terbinafine resistance in dermatophytes, where six sequential Trichophyton rubrum isolates from the same patient were found to be resistant to terbinafine and cross-resistant to other squalene epoxidase (SE) inhibitors. Microsomal SE activity from these resistant isolates was insensitive to terbinafine, suggesting a target-based mechanism of resistance (B. Favre, M. Ghannoum, and N. S. Ryder, Med. Mycol. 42:525-529, 2004). In this study, we have characterized at the molecular level the cause of the resistant phenotype of these clinical isolates. Cloning and sequencing of the SE gene and cDNA from T. rubrum revealed the presence of an intron in the gene and an open reading frame encoding a protein of 489 residues, with an equivalent similarity (57%) to both yeast and mammalian SEs. The nucleotide sequences of SE from two terbinafine-susceptible strains were identical whereas those of terbinafine-resistant strains, serially isolated from the same patient, each contained the same single missense introducing the amino acid substitution L393F. Introduction of the corresponding substitution in the Candida albicans SE gene (L398F) and expression of this gene in Saccharomyces cerevisiae conferred a resistant phenotype to the transformants when compared to those expressing the wild-type sequence. Terbinafine resistance in these T. rubrum clinical isolates appears to be due to a single amino acid substitution in SE.
Mots-clé
Amino Acid Sequence *Amino Acid Substitution Antifungal Agents/*pharmacology Cloning, Molecular Drug Resistance, Fungal/*genetics Fungal Proteins/genetics Humans Microbial Sensitivity Tests Molecular Sequence Data Naphthalenes/*pharmacology Oxygenases/chemistry/*genetics Sequence Analysis, DNA Squalene Monooxygenase Trichophyton/*drug effects
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/01/2008 16:32
Dernière modification de la notice
20/08/2019 15:51
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