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A Novel Mitochondrial Targeted Compound Phosundoxin Showing Potent Antifungal Activity against Common Clinical
Shu Zhang1,2, Yuanyuan Geng1,2, Bin Wei1
1National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China.
Abstract:
The current increase in resistance to antifungal drugs indicates that there is an urgent need to explore novel antifungal drugs with different mechanisms of action. Phosundoxin is a biphenyl aliphatic amide using a TPP-targeting strategy which targets mitochondria. To provide insights into the antifungal activities of phosundoxin, the antifungal susceptibility testing of phosundoxin was conducted on 158 pathogenic fungi and compared to that of traditional azole drugs. Phosundoxin displayed a broad-spectrum antifungal activity on all the tested yeast-like and filamentous fungi ranging from 2 to 16 mg/L. In particular, azole-resistant clinical isolates of Candida albicans were susceptible to phosundoxin with the same MICs as azole-susceptible C. albicans. Transcriptome analysis on azole-resistant C. albicans identified 554 DEGs after treatment with phosundoxin. By integrating GO and KEGG pathway enrichment analysis, the antifungal activity of phosundoxin was related to impairment of mitochondrial respiratory chain function. Acute oral and percutaneous toxicity of phosundoxin to rats showed that the compound phosundoxin were mild toxicity and LD50 was above 5000 mg/kg body weight in rats. This study demonstrated the potential of phosundoxin as an antifungal agent for the treatment of common fungal infection and contributed to providing insights into the mechanisms of action of phosundoxin against C. albicans.
Insights
Phosundoxin shows broad-spectrum antifungal activity against pathogenic fungi, including azole-resistant strains. This novel drug targets mitochondria and exhibits low toxicity, offering potential for treating fungal infections.
Area of Science:
- Mycology
- Pharmacology
- Biochemistry
Background:
- Rising antifungal drug resistance necessitates novel therapeutic agents.
- Phosundoxin is a novel biphenyl aliphatic amide targeting mitochondria via a TPP-targeting strategy.
Purpose of the Study:
- To evaluate the antifungal activity and mechanism of action of phosundoxin.
- To assess the efficacy of phosundoxin against a panel of pathogenic fungi, including azole-resistant isolates.
- To determine the toxicity profile of phosundoxin.
Main Methods:
- Antifungal susceptibility testing on 158 fungal strains.
- Comparison with traditional azole drugs.
- Transcriptome analysis and pathway enrichment analysis (GO, KEGG) on azole-resistant *Candida albicans*.
- Acute oral and percutaneous toxicity studies in rats.
Main Results:
- Phosundoxin demonstrated broad-spectrum antifungal activity (2-16 mg/L) against yeast-like and filamentous fungi.
- Effective against azole-resistant *Candida albicans* isolates with consistent Minimum Inhibitory Concentrations (MICs).
- Transcriptome analysis revealed 554 differentially expressed genes (DEGs) and indicated mitochondrial respiratory chain dysfunction.
- Phosundoxin exhibited mild toxicity in rats, with an LD50 > 5000 mg/kg.
Conclusions:
- Phosundoxin is a promising antifungal agent with broad-spectrum activity and a novel mechanism targeting mitochondrial function.
- It is effective against azole-resistant fungal strains, suggesting potential for overcoming existing resistance mechanisms.
- Phosundoxin possesses a favorable safety profile, supporting its development for treating common fungal infections.
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