A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism

Area of Science:

• Mycology
• Medicinal Chemistry
• Infectious Diseases

Background:

• Pulmonary aspergillosis, caused by *Aspergillus fumigatus*, has a high mortality rate in immunocompromised patients due to limited treatment options.
• This opportunistic fungal pathogen relies on zinc for growth and pathogenesis, suggesting zinc metabolism as a therapeutic target.

Purpose of the Study:

• To screen for novel small molecules that inhibit *Aspergillus fumigatus* growth by interfering with its zinc metabolism.
• To identify compounds with potent antifungal activity, low toxicity, and potential for in vivo efficacy against pulmonary aspergillosis.

Main Methods:

• A two-tier screening approach using resazurin and luminescence assays was employed to evaluate 59,223 small molecules.
• Compounds were tested for their effects on wild-type *A. fumigatus* under zinc-limiting conditions and a zinc transporter knockout strain under zinc-replete conditions.
• Selected compounds underwent further testing for hyphal growth inhibition, cytotoxicity in HeLa cells, and in vivo efficacy in a murine model of pulmonary aspergillosis.

Main Results:

• The initial screen identified 116 potential compounds, with six selected after rescreening, including pyrazolones, porphyrins, and polyaminocarboxylates.
• All three compound classes exhibited good in vitro antifungal activity.
• One polyaminocarboxylate compound demonstrated significant improvement in survival rates in immunosuppressed mice with pulmonary aspergillosis and showed low murine toxicity.

Conclusions:

• A novel small molecule targeting fungal zinc metabolism was identified with significant in vivo fungicidal activity and low toxicity.
• This compound represents a promising candidate for developing new therapeutic strategies against invasive fungal infections, potentially as a monotherapy or combination therapy.