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The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum
Masaki Ishii1, Tsuyoshi Yamada2,3, Kazuki Ishikawa1
1Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Tokyo, Japan.
Abstract:
The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment. Trichophyton rubrum is the most commonly isolated fungus in dermatophytosis. In T. rubrum, we identified TERG_07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast Saccharomyces cerevisiae polyamine transport kinase 2 (Ptk2), and found that T. rubrum Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both T. rubrum and S. cerevisiae, Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in S. cerevisiae. Overexpression of T. rubrum Pma1 (TrPma1) in T. rubrum Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, 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.
Insights
A newly identified fungal pathway involving TrPtk2 and TrPma1 promotes terbinafine tolerance in dermatophytes. Targeting this pathway could overcome resistance to this key antifungal drug.
Area of Science:
- Medical Mycology
- Molecular Biology
- Antifungal Drug Resistance
Background:
- Dermatophyte resistance to terbinafine is a growing clinical challenge.
- Trichophyton rubrum is a primary cause of dermatophytosis.
- Understanding resistance mechanisms is crucial for effective treatment.
Purpose of the Study:
- To investigate the molecular mechanisms underlying terbinafine tolerance in Trichophyton rubrum.
- To identify novel therapeutic targets for combating terbinafine-resistant dermatophytosis.
Main Methods:
- Gene identification and characterization of a putative protein kinase (TERG_07844) in T. rubrum.
- Comparative analysis with Saccharomyces cerevisiae Ptk2.
- Gene knockout and overexpression studies in T. rubrum and S. cerevisiae.
- Assessment of terbinafine sensitivity in wild-type and mutant strains.
- Investigation of the role of Pma1 in terbinafine tolerance.
- Testing the effect of omeprazole, a Pma1 inhibitor, on terbinafine-resistant strains.
Main Results:
- TERG_07844 was identified as T. rubrum Ptk2 (TrPtk2), an ortholog of S. cerevisiae Ptk2.
- Ptk2 knockout strains in both fungi exhibited increased sensitivity to terbinafine.
- TrPtk2-mediated terbinafine tolerance is dependent on TrPma1.
- Omeprazole enhanced terbinafine sensitivity in clinical terbinafine-resistant isolates.
Conclusions:
- The TrPtk2-TrPma1 pathway is essential for intrinsic terbinafine tolerance in dermatophytes.
- This pathway represents a potential target for combination antifungal therapies against resistant strains.
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