Back
Full-text
Journal article

Terbinafine Resistance of Trichophyton Clinical Isolates Caused by Specific Point Mutations in the Squalene Epoxidase Gene

  • Yamada, Tsuyoshi General Medical Education and Research Center, Teikyo University, Tokyo, Japan
  • Maeda, Mari Teikyo University Institute of Medical Mycology, Tokyo, Japan
  • Alshahni, Mohamed Mahdi General Medical Education and Research Center, Teikyo University, Tokyo, Japan
  • Tanaka, Reiko Medical Mycology Research Center, Chiba University, Chiba, Japan
  • Yaguchi, Takashi Medical Mycology Research Center, Chiba University, Chiba, Japan
  • Bontems, Olympia Service de Dermatologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  • Salamin, Karine Service de Dermatologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  • Fratti, Marina Service de Dermatologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  • Monod, Michel Service de Dermatologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Show more…
  • 2017-6-27
Published in:
  • Antimicrobial Agents and Chemotherapy. - American Society for Microbiology. - 2017, vol. 61, no. 7
Pharmacology (medical)
Pharmacology
Infectious Diseases
English ABSTRACT
Terbinafine is one of the allylamine antifungal agents whose target is squalene epoxidase (SQLE). This agent has been extensively used in the therapy of dermatophyte infections. The incidence of patients with tinea pedis or unguium tolerant to terbinafine treatment prompted us to screen the terbinafine resistance of all Trichophyton clinical isolates from the laboratory of the Centre Hospitalier Universitaire Vaudois collected over a 3-year period and to identify their mechanism of resistance. Among 2,056 tested isolates, 17 (≈1%) showed reduced terbinafine susceptibility, and all of these were found to harbor SQLE gene alleles with different single point mutations, leading to single amino acid substitutions at one of four positions (Leu393, Phe397, Phe415, and His440) of the SQLE protein. Point mutations leading to the corresponding amino acid substitutions were introduced into the endogenous SQLE gene of a terbinafine-sensitive Arthroderma vanbreuseghemii (formerly Trichophyton mentagrophytes) strain. All of the generated A. vanbreuseghemii transformants expressing mutated SQLE proteins exhibited obvious terbinafine-resistant phenotypes compared to the phenotypes of the parent strain and of transformants expressing wild-type SQLE proteins. Nearly identical phenotypes were also observed in A. vanbreuseghemii transformants expressing mutant forms of Trichophyton rubrum SQLE proteins. Considering that the genome size of dermatophytes is about 22 Mb, the frequency of terbinafine-resistant clinical isolates was strikingly high. Increased exposure to antifungal drugs could favor the generation of resistant strains.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/29915
Statistics
Document views: 23 File downloads:
  • fulltext.pdf: 0