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Medientyp:
E-Artikel
Titel:
Amino Acid Substitution inTrichophyton rubrumSqualene Epoxidase Associated with Resistance to Terbinafine
Beteiligte:
Osborne, Colin S.;
Leitner, Ingrid;
Favre, Bertrand;
Ryder, Neil S.
Erschienen:
American Society for Microbiology, 2005
Erschienen in:Antimicrobial Agents and Chemotherapy
Sprache:
Englisch
DOI:
10.1128/aac.49.7.2840-2844.2005
ISSN:
0066-4804;
1098-6596
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>ABSTRACT</jats:title><jats:p>There has only been one clinically confirmed case of terbinafine resistance in dermatophytes, where six sequential<jats:italic>Trichophyton rubrum</jats:italic>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<jats:italic>T. rubrum</jats:italic>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<jats:italic>Candida albicans</jats:italic>SE gene (L398F) and expression of this gene in<jats:italic>Saccharomyces cerevisiae</jats:italic>conferred a resistant phenotype to the transformants when compared to those expressing the wild-type sequence. Terbinafine resistance in these<jats:italic>T. rubrum</jats:italic>clinical isolates appears to be due to a single amino acid substitution in SE.</jats:p>