A β-amino-ketone that disrupts the fungal plasma membrane exhibits potent activity against pathogenic Trichophyton species.

Superficial fungal infections, mainly caused by dermatophytes, are a global public health issue. We evaluated the antifungal activity of six β-amino-ketones against Trichophyton rubrum, a leading agent of superficial mycoses. Among them, 3-(morpholin-4-yl)-1-phenylpropan-1-one (AB1) showed the most potent effect, with a minimum inhibitory concentration (MIC) of 7.81 µg/mL against the T. rubrum reference strain and fungicidal activity against clinical isolates, as demonstrated by minimum fungicidal concentration assays. AB1 was effective against both conidia and hyphae of T. rubrum, while showing limited activity against Candida albicans and the bacteria Escherichia coli and Staphylococcus aureus. Mechanistic studies suggest AB1 targets the fungal plasma membrane, possibly via ergosterol interactions, supported by increased MICs in ergosterol-rich conditions and membrane integrity assays. Confocal microscopy revealed morphological alterations in AB1-treated hyphae, indicative of membrane damage. Transmission electron microscopy confirmed cytoplasmic disorganization and membrane disruption at subinhibitory concentrations. Toxicological assays showed moderate cytotoxicity in human fibroblasts (IC50 = 37.75 µg/mL) and no toxicity in Galleria mellonella larvae at high doses. These findings highlight AB1 as a promising antifungal candidate against Trichophyton spp., with the potential benefit of reduced impact on the host microbiota compared to broad-spectrum antimicrobials.