In vitro interactions between 17-AAG and azoles against Exophiala dermatitidis

Area of Science:

• Mycology
• Infectious Diseases
• Pharmacology

Background:

• Exophiala dermatitidis causes infections that are difficult to treat.
• Heat shock protein 90 (Hsp90) is crucial for fungal stress response and antifungal resistance.
• Targeting Hsp90 with inhibitors presents a potential combination strategy for antifungal therapy.

Purpose of the Study:

• To evaluate the antifungal activity of 17-AAG, an Hsp90 inhibitor, alone and in combination with azole antifungals.
• To investigate the efficacy of this combination against clinical isolates of Exophiala dermatitidis.

Main Methods:

• In vitro evaluation using broth microdilution chequerboard assays.
• Testing combinations of 17-AAG with itraconazole, voriconazole, and posaconazole.
• Utilized 18 clinical isolates of Exophiala dermatitidis and Candida parapsilosis for quality control.

Main Results:

• 17-AAG alone demonstrated minimal antifungal activity.
• Synergistic effects were observed between 17-AAG and posaconazole (83.3%), itraconazole (66.7%), and voriconazole (5.6%).
• Effective concentrations for synergistic combinations were primarily within the 2-8 μg/mL range, with no antagonism noted.

Conclusions:

• Combining 17-AAG with azoles, particularly posaconazole and itraconazole, shows significant synergistic antifungal activity against Exophiala dermatitidis.
• This approach may offer a novel therapeutic option for challenging Exophiala dermatitidis infections.
• Further research is needed to develop host-specific Hsp90 inhibitors due to the toxicity of 17-AAG.