Terbinafine Resistance of dermatophyte species Caused by Point Mutations in the Squalene Epoxidase Gene

Introduction and Objectives: With regard to increasing number of antifungal-resistant dermatophytes, antifungal susceptibility testing of dermatophytes serves as a useful tool in managing clinical dermatophytosis. Terbinafine is one of the allylamine antifungal agents whose target is squalene epoxidase (SQLE). Terbinafine resistance has been predominately attributed to point mutations in SQLE target gene a key enzyme in the ergosterol biosynthetic pathway leading to single amino acid substitutions. Inhibition of this enzyme leads to accumulation of squalene inside the fungal cells, depletion of ergosterol, and finally causes cell death. This study aimed to determine point mutations in terbinafine-resistant isolates. Materials and Methods: Dermatophyte species (n= 99) was confirmed by sequencing of ITS region. Antifungal susceptibility testing of all isolates was assessed to terbinafine agent using CLSI M38-A2 guidelines. Results: Based on our results, among 99 tested isolates, 5 (5%) showed reduced terbinafine susceptibility (MIC> 32 μg/ml), of which for two species T. rubrum and T. tonsurans were found to be related to amino acid substitution Leu393 by Phe in the squalene epoxidase protein. We reported terbinafine resistance for dermatophytes isolated from tinea pedis and tinea corporis. This is the first case of terbinafine-resistant T. tonsurans strain isolated from patient. Previous studies showed T. rubrum isolates resistant to TER were fully cross-resistant to naftifine, butenafine, and tolnaftate. Therefore, it is suggested antifungal susceptibility testing of isolates resistant to TER against the mentioned antifungals. Conclusion: This increase of terbinafine resistance of dermatophyte isolates is worrisome warranting antifungal susceptibility testing and mutation analysis for monitoring this emerging resistance.

Keywords:

Squalene epoxidase , Point mutation , Terbinafine resistance