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  • Could the antifungal terbinafine be working through a dual action?

    BethBradshaw's picture

    Terbinafine (Lamisil) is an allylamine antifungal that  can be applied to skin to treat dermatophyte infections such as jock itch (tinea cruris), athlete's foot (tinea pedis) and ringworm (tinea corporis), or taken by mouth to treat fungal nail or scalp infections. It works by inhibiting the enzyme squalene epoxidase, which ultimately stops the fungus from producing the ergosterol it needs for its cell membrane. Ergosterol is used by fungi and some parasites (e.g. trypanosomes), but not humans, which makes this pathway a particularly good source of drug targets. Indeed, azole antifungals inhibit the next enzyme in the pathway, while amphotericin B targets ergosterol directly.

    A recent study found that terbinafine also has a second, unrelated mode of action: it is a specific activator of the TASK3 protein. TASK3 allows potassium to ‘leak’ across the cell membrane and is involved in many cell processes. Yeast has a related protein, TOK1, so the authors of the study speculate whether the antifungal activity of terbinafine might be partly acting through this mechanism, but further research would be required to demonstrate this.

    Mutations in the KCNK9 gene (on chromosome 8) that encodes TASK3 in humans are the cause of Birk-Barel syndrome, an inherited rare disease that involves some of all of the following symptoms: feeding difficulties, decreased muscle tone, intellectual disability, characteristic facial features, high or cleft palate. The authors of the study say that terbinafine is most likely too toxic to be used directly as a treatment for Birk-Barel, although another TASK3 activators called mefanamic acid has been tried with some tentative success.