Affiliation:
1. Infectious Diseases, Novartis Institutes for BioMedical Research, 1235 Vienna, Austria
Abstract
ABSTRACT
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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