Abstract
The critical CO2 hydration reaction to bicarbonate and protons is catalyzed by carbonic anhydrases (CAs, EC 4.2.1.1). Their physiological role is to assist the transport of the CO2 and HCO3− at the cellular level, which will not be ensured by the low velocity of the uncatalyzed reaction. CA inhibition may impair the growth of microorganisms. In the yeasts, Candida albicans and Malassezia globosa, the activity of the unique β-CA identified in their genomes was demonstrated to be essential for growth of the pathogen. Here, we decided to investigate the sulfonamide inhibition profile of the homologous β-CA (MreCA) identified in the genome of Malassezia restricta, an opportunistic pathogen triggering dandruff and seborrheic dermatitis. Among 40 investigated derivatives, the best MreCA sulfonamide inhibitors were dorzolamide, brinzolamide, indisulam, valdecoxib, sulthiam, and acetazolamide (KI < 1.0 μM). The MreCA inhibition profile was different from those of the homologous enzyme from Malassezia globosa (MgCA) and the human isoenzymes (hCA I and hCA II). These results might be useful to for designing CA inhibitor scaffolds that may selectively inhibit the dandruff-producing fungi.
Highlights
The scalp has a high follicular density and an enhanced sebum production rate compared to other human skin areas [1]
We recently proposed exploring certain members of the ancient superfamily of ubiquitous metalloenzymes, known as carbonic anhydrases
CA inhibitors (CAIs) belonging to sulfonamide, thiol or DTC
Summary
The scalp has a high follicular density and an enhanced sebum production rate compared to other human skin areas [1]. Dandruff has been considered as a less severe form of scalp seborrheic dermatitis, characterized by skin flacking, sub-inflammation, pruritus, and absence of erythema Both scalp conditions are related to higher levels of the lipophilic yeasts belonging to the genera Malassezia (e.g., M. globosa and M. restricta) [1,2]. A dandruff mouse model revealed that treatment with sulfonamides resulted in fragmented fungal hyphae, as occurs with ketoconazole, a clinically-used antifungal agent [24] In this context, we decided to investigate the sulfonamide inhibition profile of the homologous β-CA (acronym MreCA) recently identified in the genome of M. restricta [8,18], which cooperates with M. globosa and the bacterial scalp in triggering dandruff and seborrheic dermatitis [25,26]. The MreCA sulfonamide inhibition profile was compared with those reported for the two human α-CA isoforms (hCA I and hCA II) and the β-CA from M. globosa with the intent to select new potential anti-dandruff and anti-seborrheic dermatitis compounds
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