The Ptk2-Pma1 pathway enhances tolerance to terbinafine inTrichophyton rubrum

Abstract

AbstractThe increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment.Trichophyton rubrumis the most commonly isolated fungus in dermatophytosis. InT. rubrum, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeastSaccharomyces cerevisiaepolyamine transport kinase 2 (Ptk2) and found thatT. rubrumPtk2 (TrPtk2) is involved in terbinafine tolerance. In bothT. rubrumandS. cerevisiae, Ptk2 knockout strains were more sensitive to terbinafine compared to the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. TheT. rubrumPtk2 knockout strain (ΔTrPtk2) was sensitive to omeprazole, an inhibitor of plasma membrane proton pump Pma1, which is activated through phosphorylation by Ptk2 inS. cerevisiae. Overexpression ofT. rubrumPma1 (TrPma1) in ΔTrPtk2 suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine- resistant dermatophytes.