Abstract
PurposeAspergillus and Fusarium molds cause blinding corneal infections as a consequence of ocular trauma and in association with contact lens wear. As these fungi require zinc for fungal growth, we examined the effect of atovaquone, a ubiquinone analog that disrupts zinc homeostasis, on fungal growth in vitro and in vivo.MethodsIn vitro: Aspergillus and Fusarium germinating conidia were incubated overnight with atovaquone, and hyphal growth was measured by fluorimetry. In vivo: C57BL/6 mouse corneas were infected with Aspergillus or Fusarium conidia. Atovaquone was added topically and corneal opacification and fungal growth were quantified.ResultsAtovaquone has antifungal activity against Aspergillus and Fusarium clinical isolates, with Fusarium species being more sensitive to atovaquone than Aspergillus species. Atovaquone also reduced labile intracellular zinc levels and increased the sensitivity of Aspergillus to metal shock. Atovaquone reduced vacuolar acidification, which regulates storage of intracellular free zinc, and also acted synergistically with voriconazole and itraconazole to kill hyphae. Furthermore, mitochondrial potential and ATP production were reduced in both Aspergillus and Fusarium following atovaquone treatment. Finally, topical application of atovaquone to the ocular surface significantly inhibited fungal growth and corneal opacification in murine models of fungal keratitis.ConclusionsThese studies demonstrate that atovaquone has pronounced in vitro and in vivo antifungal activity against filamentous fungi by disrupting both metal homeostasis and mitochondrial function, and therefore has potential as a novel antifungal agent.
Highlights
Title Atovaquone Impairs Growth of Aspergillus and Fusarium Keratitis Isolates by Modulating Mitochondrial Function and Zinc Homeostasis
Aspergillus and Fusarium are filamentous molds that are ubiquitous in the environment; they can cause severe pulmonary, dermatologic, and systemic infections in patients with genetic or induced immune deficiencies, which frequently results in death from uncontrolled fungal growth.[1,2,3,4]
Fusarium species are an important cause of contact lens– related corneal infections in immune-competent individuals in the industrialized world, and Fusarium and Aspergillus corneal ulcers are common in developing countries following ocular injury and penetration of spores to the corneal stroma.[5,6,7]
Summary
Title Atovaquone Impairs Growth of Aspergillus and Fusarium Keratitis Isolates by Modulating Mitochondrial Function and Zinc Homeostasis. Atovaquone Impairs Growth of Aspergillus and Fusarium Keratitis Isolates by Modulating Mitochondrial Function and Zinc Homeostasis. Aspergillus and Fusarium molds cause blinding corneal infections as a consequence of ocular trauma and in association with contact lens wear. As these fungi require zinc for fungal growth, we examined the effect of atovaquone, a ubiquinone analog that disrupts zinc homeostasis, on fungal growth in vitro and in vivo
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