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

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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.
Funding Information
  • National Institutes of Health (R01HL62150-32)
  • Division of Microbiology and Infectious Diseases (1R21AI200456-01)

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