Translation Inhibition by Rocaglamide A Enhances Susceptibility of Yeasts to Caspofungin

Area of Science:

• Molecular Biology
• Mycology
• Antimicrobial Drug Development

Background:

• Fks1 is crucial for fungal cell wall synthesis and a target for caspofungin.
• Fks1 mutations cause caspofungin resistance by impairing drug interaction.
• FKS1 mRNA translation relies on translation initiation helicases eIF4A and Ded1.

Purpose of the Study:

• To investigate the effect of eIF4A inhibitor Rocaglamide A (RocA) and Ded1 mutation on FKS1 translation.
• To assess the impact on caspofungin susceptibility in Saccharomyces cerevisiae and Candida glabrata.
• To explore targeting translation initiation helicases as a strategy to overcome caspofungin resistance.

Main Methods:

• Utilized wild-type and temperature-sensitive ded1-ts strains of Saccharomyces cerevisiae.
• Treated fungal cells with Rocaglamide A and/or caspofungin.
• Monitored fungal growth inhibition, translation repression, and drug susceptibility.

Main Results:

• RocA treatment enhanced caspofungin-induced growth inhibition and translation repression.
• ded1-ts strains showed increased sensitivity to both RocA and caspofungin.
• Combination therapy of RocA and caspofungin demonstrated fungicidal activity in both S. cerevisiae and C. glabrata.

Conclusions:

• Targeting the Ded1 helicase can be a strategy to prevent caspofungin resistance.
• Combining RocA with caspofungin shows potential for treating pathogenic yeasts.
• Translation initiation helicases represent promising targets for novel combination antifungal therapies.