Novel Potential Antifungal Compounds With Dual Mechanism Of Action Selectively Acting Against Malassezia spp.

Malassezia spp. infections and azole drug resistance phenomena are of great concern in both human and veterinary medicine. Malassezia spp. cause severe human and animal skin disorders, with a zoonotic potential for M. pachydermatis, which could include it on WHO fungal pathogens priority list. Inorganic SeS2 is used as topical treatment, but its mechanism of action on fungal sterol pathways has not been fully revealed, due to the great variability of lipidome among Malasseziomycetes. In this work we evaluated antifungal activity by microdilution broth assay of novel compounds with acyl/selenoureido moieties and primary/secondary sulfonamide groups with a dual mechanism of action: (i) a selective organic selenium fungal toxicity and (ii) the inhibition of a new antifungal target metalloenzyme, the Carbonic Anhydrases (CAs, EC 4.2.1.1). Minimal Inhibitory Concentration (MIC) values of selenium-containing compounds showed very high activity on M. pachydermatis (0,5-3,33 μg/ml) instead of C. albicans and C. glabrata (3,33-256 μg/ml). Suppression of antifungal activity was noted when selenium was replaced with either chalcogen isosteric elements oxygen and sulfur. Compounds library was also tested on M. furfur and M. globosa showing preferential activity on M. pachydermatis, with only a few candidates more active on M. furfur. Cytotoxicity properties of selected compounds against MDBK and HaCat cells were assessed, which showed safety profile at MIC values, better than SeS2. KI values on Malassezia spp. CAs of compounds bearing primary or secondary sulfonamide moiety was in the low-medium nanomolar range, demonstrating a multitarget selective activity on Malassezia spp., probably depending on lipidome constitution.