Terbinafine resistance of Trichophyton clinical isolates caused by specific point mutations in the squalene epoxidase gene [PublishAheadOfPrint]

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 terbinafine resistance of all Trichophyton clinical isolates from the laboratory of Centre Hospitalier Universitaire Vaudois collected over a three-year period, and to identify their mechanism of resistance. Among 2056 tested isolates, 17 ( 1%) showed reduced terbinafine susceptibility, all of which 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 T. mentagrophytes) strain. All of the generated A. vanbreuseghemii transformants expressing mutated SQLE proteins exhibited obvious terbinafine-resistant phenotypes compared to the parent strain and to transformants expressing wild-type SQLE proteins. Nearly identical phenotypes were also observed in A. vanbreuseghemii transformants expressing mutant forms of T. 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.

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