Anti-Fungal and Toxicology Assessment of ISFP10, an Inhibitor of Fungal Phosphoglucomutase (PGM).

Abstract

Background and objective: The novel small molecule ISFP10 inhibits fungal phosphoglucomutase (PGM) activity in Aspergillus fumigatus and Pneumocystis spp. With 50-fold selectivity over the human isoform, conferred by a conserved cysteine residue present in several pathogenic fungi, ISFP10 may represent a promising broad-spectrum antifungal. We evaluated its activity against Candida albicans and Candida glabrata, followed by toxicology assessment in mice.

Methods: Minimum inhibitory concentration susceptibilities were performed on three strains of C. albicans and C. glabrata and compared with fluconazole. Growth inhibition was further assessed in an 8-h, concentration-dependent growth assay. For toxicology, C57BL6 mice received once-daily intraperitoneal injections of vehicle control (dimethyl sulfoxide) or ISFP10 (10 mg/kg) for 7 days. Body weight, complete blood count (CBC), blood chemistry, histopathology of major organs, and lung extracellular matrix (ECM) and cytokine levels (ELISA, qPCR) were analyzed.

Results: ISFP10 inhibited all tested Candida strains with significantly greater potency than fluconazole. It also showed concentration-dependent inhibition of growth in liquid culture. In mice, no significant differences in daily or final body weight, ECM transcript levels, or interleukin (IL)-6 expression were observed between groups. Tumor necrosis factor-α (TNFα) levels in lung tissue were significantly reduced in ISFP10-treated animals, suggesting a potential anti-inflammatory effect. Blood chemistry and CBC revealed minor abnormalities (increased neutrophils, decreased potassium), but these were not clinically significant. Histopathologic evaluation showed no evidence of organ toxicity.

Conclusions: ISFP10 demonstrates potent antifungal properties against C. albicans and C. glabrata and a favorable safety profile in vivo, supporting its further development as a potential broad-spectrum antifungal agent.