Leveraging Vulnerabilities in Copper Trafficking for Synergistic Antifungal Activity.

Area of Science:

• Mycology
• Medical Biochemistry
• Drug Discovery

Background:

• * *Candida albicans* is an opportunistic pathogen causing millions of infections annually, necessitating novel and effective treatments.
• * Azole antifungals induce stress responses in *C. albicans*, particularly affecting metal-dependent processes.
• * Metallohomeostasis vulnerabilities under drug stress present a potential therapeutic target.

Purpose of the Study:

• * To investigate if disrupting copper (Cu) trafficking can enhance antifungal efficacy against *C. albicans*.
• * To explore the mechanisms by which copper chelators interact with azole antifungals.
• * To identify key cellular processes regulated by copper homeostasis in *C. albicans*.

Main Methods:

• * Proteomic analysis to identify differentially expressed proteins under TTM treatment.
• * Biochemical assays to assess enzyme activity and protein stability.
• * Growth inhibition assays to evaluate antifungal activity and synergy.

Main Results:

• * Tetrathiomolybdate (TTM) alone inhibits *C. albicans* growth and synergizes with azoles.
• * TTM alters protein expression related to fermentation and oxidative stress response.
• * Synergy is linked to TTM-induced destabilization of CuZn superoxide dismutase 1, increasing nitric oxide dioxygenase Yhb1 stability, which is then inhibited by azoles.

Conclusions:

• * Copper homeostasis is central to *C. albicans* fitness, linking energy production and oxidative stress management.
• * Pharmacological manipulation of copper trafficking offers a strategy to enhance existing antifungal therapies.
• * TTM and azole combination therapy presents a promising avenue for more efficacious antifungal treatments.