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Antimicrobial Agents and Chemotherapy, July 2005, p. 2840-2844, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2840-2844.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Amino Acid Substitution in Trichophyton rubrum Squalene Epoxidase Associated with Resistance to Terbinafine

Colin S. Osborne,* Ingrid Leitner, Bertrand Favre,{dagger} and Neil S. Ryder{ddagger}

Infectious Diseases, Novartis Institutes for BioMedical Research, 1235 Vienna, Austria

Received 31 January 2005/ Returned for modification 11 February 2005/ Accepted 10 April 2005

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.

* Corresponding author. Mailing address: Infectious Diseases, Room 8654, Novartis Institutes for BioMedical Research, Inc., 100 Technology Square, Cambridge, MA 02139. Phone: (617) 871-3142. Fax: (617) 871-7047. E-mail: colin.osborne{at}pharma.novartis.com.

{dagger} Present address: Department of Dermatology, Hospital of Beaumont CHUV, 1011 Lausanne, Switzerland.

{ddagger} Present address: Novartis Institutes for Biomedical Research, Inc., Cambridge, MA 02139.

Antimicrobial Agents and Chemotherapy, July 2005, p. 2840-2844, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.2840-2844.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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