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Updated: May 2, 2026
Exploring Mitochondrial Energy Metabolism of Single 3D Microtissue Spheroids Using Extracellular Flux Analysis
Published on: February 3, 2022
Effects of the novel mitochondrial targeted compound phosundoxin against Sporothrix globosa: Microbial sensitivity
Hanyue Sheng1,2, Shu Zhang2, Wenjing Zhu1
1Department of Dermatology, The Second Hospital of Jilin University, Changchun, Jilin 130041, China.
Abstract:
In recent years, the resistance of Sporothrix globosa to antifungal treatments has steadily increased, while the cure rate for sporotrichosis has declined. This growing resistance underscores the urgent need to develop novel antifungal agents with distinct mechanisms of action. Previous studies have demonstrated that phosundoxin, a biphenyl aliphatic amide that targets mitochondria, exhibits potent inhibitory effects against a broad spectrum of fungi. To further evaluate its antifungal activity, we conducted drug susceptibility testing on 112 S. globosa strains and compared the results with those of conventional antifungal agents. Phosundoxin consistently exhibited antifungal activity against all tested strains, including both mycelial forms and 32 yeast-phase strains, at concentrations ranging from 1 to 4 µg/ml. Notably, in itraconazole-resistant S. globosa strains, phosundoxin treatment led to the identification of 553 differentially expressed genes and 273 differentially expressed proteins. Integrated Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed that phosundoxin exerts its antifungal effects by disrupting the mitochondrial respiratory chain and oxidative phosphorylation. This disruption triggers cellular stress responses, including the upregulation of ammonia transport and nitrogen metabolism. Additionally, phosundoxin treatment weakens cellular defense mechanisms, interferes with the cell cycle, and inhibits protein synthesis-ultimately leading to negative regulatory effects and cell death. These findings highlight phosundoxin's potential as a novel antifungal agent for treating S. globosa infections and provide critical insights into its mechanism of action against this pathogen.
Insights
Phosundoxin shows potent antifungal activity against Sporothrix globosa, including resistant strains. This novel agent disrupts fungal mitochondria, offering a promising new treatment for sporotrichosis.
Area of Science:
- Mycology
- Antimicrobial Resistance
- Drug Discovery
Background:
- Increasing resistance of Sporothrix globosa to antifungals necessitates new treatments.
- Sporotrichosis cure rates are declining due to antifungal resistance.
- Phosundoxin, a mitochondrial-targeting agent, shows broad-spectrum antifungal potential.
Purpose of the Study:
- To evaluate the antifungal activity of phosundoxin against Sporothrix globosa.
- To compare phosundoxin's efficacy with conventional antifungal agents.
- To elucidate the mechanism of action of phosundoxin against S. globosa.
Main Methods:
- Drug susceptibility testing on 112 S. globosa strains.
- Comparative analysis with conventional antifungal agents.
- Gene and protein expression analysis (differentially expressed genes and proteins) in itraconazole-resistant strains.
- Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis.
Main Results:
- Phosundoxin demonstrated consistent antifungal activity against all tested S. globosa strains (mycelial and yeast forms) at 1-4 µg/ml.
- Treatment of itraconazole-resistant strains revealed 553 differentially expressed genes and 273 differentially expressed proteins.
- Phosundoxin disrupts the mitochondrial respiratory chain and oxidative phosphorylation.
- Phosundoxin induces cellular stress responses, including ammonia transport and nitrogen metabolism upregulation.
- Phosundoxin weakens cellular defenses, interferes with the cell cycle, and inhibits protein synthesis, leading to cell death.
Conclusions:
- Phosundoxin exhibits significant potential as a novel antifungal agent for Sporothrix globosa infections.
- The mechanism of action involves mitochondrial disruption, cellular stress, and inhibition of vital cellular processes.
- Phosundoxin offers a promising alternative for treating challenging sporotrichosis cases, especially those resistant to existing therapies.
