Malassezia spp. carbonic anhydrases.

Abstract

Carbonic anhydrases (CAs) are essential metalloenzymes that catalyse the reversible conversion of CO₂ to bicarbonate, playing a crucial role in pH regulation, CO₂ sensing, and metabolic homeostasis. In Malassezia species, β-class CAs have emerged as promising drug targets for antifungal and dermatological applications, particularly in conditions such as dandruff and seborrheic dermatitis. Among the studied Malassezia species, the carbonic anhydrases from M. globosa (MgCA), M. restricta (MreCA) and M. pachydermatis (MpaCA) have been extensively characterized, demonstrating significant functional differences in both inhibition and activation mechanisms. This chapter explores the inhibition of Malassezia CAs using diverse classes of inhibitors, including sulfonamides, boronic acids, phenols, dithiocarbamates, and benzoxaboroles. Many of these compounds exhibit selective inhibition of fungal CAs over human isoforms, underscoring their potential as novel antifungal agents. Additionally, activation studies have revealed that both MgCA and MreCA can be modulated by biogenic amines and amino acids, with MreCA displaying markedly higher sensitivity, particularly to catecholamines like L-adrenaline, suggesting a potential link between stress responses and fungal virulence. The differential inhibition and activation profiles of Malassezia β-CAs provide valuable insights into fungal physiology, enzyme regulation, and potential therapeutic interventions. These findings establish a strong foundation for the rational design of selective inhibitors and activators that could serve as next-generation antifungal agents.