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Leveraging Vulnerabilities in Copper Trafficking for Synergistic Antifungal Activity
Catherine A Denning-Jannace1, Katherine J James1, Carlos R Monteagudo1
1Department of Chemistry, Duke University, French Family Science Center, 124 Science Drive, Durham, North Carolina 27708, United States.
Abstract:
Candida albicans is an opportunistic fungal pathogen that causes millions of infections per year, for which more efficacious treatments are needed. Observations that azole antifungals incite C. albicans to adjust a variety of metal-dependent processes led us to hypothesize that vulnerabilities in metallohomeostasis incurred by drug stress could be leveraged by compounds that interrupt metal trafficking. Here, we show that tetrathiomolybdate (TTM), a copper (Cu) chelator that interferes with Cu trafficking and use, inhibits growth of C. albicans on its own and synergizes with select azoles to enhance antifungal activity. Proteomic and biochemical experiments revealed that TTM causes differential expression and stabilization of proteins involved in fermentation and oxidative stress responses in C. albicans. The synergy between TTM and azoles was found to arise from increased expression and stability of the nitric oxide dioxygenase Yhb1, a response driven by the decreased stability and activity incurred by TTM of CuZn superoxide dismutase 1. Addition of imidazole-based antifungals highjacks this stress response by inhibiting Yhb1. This study highlights the centrality of Cu homeostasis as a regulatory hub connecting energy production, oxidative stress management, and overall cellular fitness in ways that can be pharmacologically manipulated to enhance efficacy of existing antifungal agents.
Insights
Tetrathiomolybdate (TTM), a copper chelator, inhibits Candida albicans growth and enhances azole antifungal efficacy. This occurs by disrupting copper homeostasis, impacting stress responses and energy production for improved antifungal strategies.
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.
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