A β-amino-ketone that disrupts the fungal plasma membrane exhibits potent activity against pathogenic <i>Trichophyton</i> 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 <i>Trichophyton rubrum</i>, a leading agent of superficial mycoses. Among them, 3-(morpholin-4-yl)-1-phenylpropan-1-one (<b>AB1</b>) showed the most potent effect, with a minimum inhibitory concentration (MIC) of 7.81 µg/mL against the <i>T. rubrum</i> reference strain and fungicidal activity against clinical isolates, as demonstrated by minimum fungicidal concentration assays. <b>AB1</b> was effective against both conidia and hyphae of <i>T. rubrum</i>, while showing limited activity against <i>Candida albicans</i> and the bacteria <i>Escherichia coli</i> and <i>Staphylococcus aureus</i>. Mechanistic studies suggest <b>AB1</b> 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 <b>AB1</b>-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 <i>Galleria mellonella</i> larvae at high doses. These findings highlight <b>AB1</b> as a promising antifungal candidate against <i>Trichophyton</i> spp., with the potential benefit of reduced impact on the host microbiota compared to broad-spectrum antimicrobials.