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The Ptk2-Pma1 pathway enhances tolerance to terbinafine in Trichophyton rubrum

Summary

Researchers discovered that a protein called TrPtk2 helps dermatophytes resist terbinafine, a common antifungal medicine. They found that blocking this protein makes the fungus more susceptible to terbinafine. Additionally, they discovered that omeprazole, a stomach medication approved for human use, can be combined with terbinafine to make it more effective against resistant fungal infections.

Background

Terbinafine-resistant dermatophytes have emerged in recent years, with Trichophyton rubrum being the most commonly isolated fungus in dermatophytosis. Previous research identified squalene epoxidase mutations as causes of terbinafine resistance, but therapeutic targets to alleviate this resistance remain to be identified.

Objective

To identify genes involved in terbinafine tolerance in T. rubrum and investigate the potential of combining terbinafine with other agents to overcome resistance in dermatophytes.

Results

TERG_07844 deletion resulted in increased terbinafine sensitivity in T. rubrum, and this gene product is functionally similar to S. cerevisiae Ptk2. Overexpression of TrPma1 suppressed terbinafine sensitivity in the Ptk2 knockout strain, indicating TrPma1 functions downstream of TrPtk2. Omeprazole, a proton pump inhibitor, enhanced terbinafine sensitivity in both susceptible and resistant clinical isolates.

Conclusion

The TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and serves as a potential target for combinational antifungal therapy. Omeprazole, an FDA-approved drug, may be repurposed to enhance terbinafine efficacy against resistant dermatophytes.
  • Published in:Antimicrobial Agents and Chemotherapy,
  • Study Type:Experimental Study,
  • Source: 38567956
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