Managing Malassezia species and related infections: new insights into recent natural and synthetic antifungal compounds and their mechanism of action

Abstract Malassezia spp. are lipophilic yeasts that colonize human and animal skin, being implicated in several dermatological and systemic disorders, including seborrheic dermatitis, pityriasis versicolor, and opportunistic fungemia in immunocompromised individuals. The increasing diffusion of resistant strains and the limited efficacy of conventional azole-based antifungal therapies have prompted the search for alternative treatment strategies. This review explores recent approaches to fighting Malassezia , focusing on both natural and synthetic compounds targeting key molecular pathways. Among the most innovative approaches are Malassezia carbonic anhydrases, essential enzymes involved in pH regulation and cellular metabolism, which represent promising and selective antifungal targets. The antifungal potential of plant-derived extracts rich in polyphenols, terpenoids, and flavonoids is also discussed, highlighting their ability to interfere with yeast growth and adhesion. Silver nanoparticles are examined as synergistic agents due to their antimicrobial properties and potential as carriers for natural bioactive compounds. Additional perspectives include the use of probiotics/postbiotics to restore skin microbiota balance, enzymes such as chitinase and chitosanase, and the inhibition of lipases, key enzymes in Malassezia lipid metabolism. Finally, the growing interest in antimicrobial peptides, both natural and synthetic, opens new avenues for targeted topical formulations. Overall, the integration of natural and synthetic approaches, supported by a deeper understanding of Malassezia ’s molecular mechanisms, may promote the development of more effective and safer multifactorial therapies. Graphical abstract