Repurposing an inhibitor of ribosomal biogenesis with broad anti-fungal activity

Area of Science:

• Mycology
• Medicinal Chemistry
• Drug Discovery

Background:

• The increasing threat of drug-resistant fungal infections necessitates novel antifungal agents.
• Existing antifungal therapies face limitations, including resistance development and toxicity concerns.

Purpose of the Study:

• To identify novel antifungal compounds with unique mechanisms of action.
• To evaluate the antifungal potential of NSC319726, a thiosemicarbazone, against human pathogenic fungi.

Main Methods:

• Screening approximately 3000 compounds against Candida species, Aspergillus fumigatus, and Cryptococcus neoformans.
• Assessing antifungal activity, synergy with existing antifungals (azoles, caspofungin), and in vitro toxicity (IC50 vs. MIC50).
• Conducting transcriptome analysis of *Candida albicans* treated with NSC319726 using Gene Ontology (GO).

Main Results:

• NSC319726 demonstrated broad-spectrum antifungal activity (0.1-2.0 µg/ml), including against fluconazole-resistant *Candida* isolates.
• Synergistic effects were observed when NSC319726 was combined with azoles and caspofungin.
• Transcriptome analysis revealed downregulation of genes involved in protein translation and ribosome biogenesis in treated *C. albicans*.
• NSC319726 exhibited low in vitro toxicity to human cells.

Conclusions:

• NSC319726 is a promising repurposed compound with significant antifungal potential against key human pathogens.
• Its broad activity, synergistic properties, and low toxicity warrant further investigation, including in vivo studies for candidiasis treatment.