How a Fungal Pathway Increases Drug Resistance

Jim Crocker
5th April, 2024

How a Fungal Pathway Increases Drug Resistance

Image Source: Natural Science News, 2024

Key Findings

  • Researchers at Musashino University found a gene in a fungus causing skin infections that contributes to drug resistance
  • Deactivating this gene made the fungus more sensitive to the antifungal drug terbinafine
  • A common acid reflux medication increased the effectiveness of terbinafine against resistant fungal strains
Dermatophytes are a group of fungi responsible for skin infections like athlete's foot and nail fungus, which can be difficult to treat. One of the most common culprits is Trichophyton rubrum. A widely used drug for these infections is terbinafine, but there's a growing concern: these fungi are becoming increasingly resistant to the medication. This resistance is a barrier to successful treatment and poses a challenge for healthcare providers and patients alike. In a recent study by Musashino University, researchers have made a significant discovery that could pave the way for better treatment strategies against these stubborn infections[1]. They've identified a gene in T. rubrum, called TERG_07844, which is similar to a gene in baker's yeast that controls the uptake of polyamines, a type of organic compound. The protein produced by this gene, named Trichophyton rubrum Ptk2 (TrPtk2), was found to be involved in the fungus's tolerance to terbinafine. The study revealed that when the TrPtk2 gene was deactivated in T. rubrum, the resulting fungal strains were more susceptible to terbinafine. This increased sensitivity was also observed in similar experiments with baker's yeast, indicating that the role of Ptk2 in drug tolerance is conserved across different fungal species. Digging deeper, the team discovered that a protein called Pma1, which is involved in controlling the acid balance in fungal cells, is activated by Ptk2. When they increased the amount of Pma1 in the TrPtk2-deactivated T. rubrum strains, they found that the fungi's sensitivity to terbinafine decreased. This suggests that Pma1 is a key player in the pathway that allows T. rubrum to tolerate terbinafine. Interestingly, when the researchers used omeprazole, a drug commonly used to treat acid reflux in humans and known to inhibit Pma1, they found that it increased the terbinafine sensitivity of terbinafine-resistant T. rubrum strains. This indicates that targeting the TrPtk2-TrPma1 pathway could be a promising strategy in overcoming terbinafine resistance. These findings are particularly relevant in light of previous studies that have documented the emergence of terbinafine resistance in T. rubrum. For instance, a study in Japan reported a strain of T. rubrum with low susceptibility to terbinafine, highlighting the need for alternative treatments[2]. Another study identified a single amino acid change in the enzyme targeted by terbinafine, which led to the resistance observed in clinical isolates[3]. Additionally, resistance has been observed in patients who did not respond to terbinafine therapy, with subsequent analysis revealing a primary resistance to the drug[4]. The current research builds on these earlier findings by not only confirming the existence of terbinafine resistance but also by identifying a new genetic factor contributing to this resistance. Moreover, it offers a potential solution by suggesting that inhibiting the TrPtk2-TrPma1 pathway could restore the effectiveness of terbinafine. The implications of this study are significant. It opens the door to developing combination therapies that use existing drugs like omeprazole alongside terbinafine to treat resistant fungal infections. It also provides a deeper understanding of the genetic mechanisms behind drug resistance in fungi, which is essential for the development of new antifungal agents. In conclusion, the Musashino University study offers a ray of hope in the fight against terbinafine-resistant dermatophytes. By revealing the genetic basis for this resistance and suggesting a novel treatment approach, it lays the groundwork for more effective therapies and could potentially improve outcomes for patients suffering from stubborn fungal infections.

BiotechGeneticsBiochem

References

Main Study

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

Published 3rd April, 2024

https://doi.org/10.1128/aac.01609-23

Related Studies

2) Discovery of Terbinafine Low Susceptibility Trichophyton rubrum strain in Japan.

https://doi.org/10.4265/bio.23.151

3) Amino acid substitution in Trichophyton rubrum squalene epoxidase associated with resistance to terbinafine.

Journal: Antimicrobial agents and chemotherapy, Issue: Vol 49, Issue 7, Jul 2005

4) Clinical Trichophyton rubrum strain exhibiting primary resistance to terbinafine.

Journal: Antimicrobial agents and chemotherapy, Issue: Vol 47, Issue 1, Jan 2003


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