Insights into the role of sphingolipids in antifungal drug resistance

Sphingolipids are major constituents of the plasma membrane that can act as structural and signalling molecules in diverse organisms such as animals, plants, and fungi. The metabolism of sphingolipids in fungi has gained increasing attention due to its relevance in the context of pathogenicity and therapeutic intervention for fungal infections. Humans are susceptible to a variety of fungal infections, which can range from superficial infections on the skin and mucosal surfaces to life-threatening systemic and invasive infections. Additionally, immunocompromised individuals are more prone to developing systemic infections caused by Candida, Aspergillus, and Cryptococcus spp., which are difficult to treat and have a high risk of morbidity and mortality. Several antifungal drugs have been given clinical approval to treat systemic and invasive fungal infections, however, pathogenic fungi have the intrinsic capacity to evolve different resistance mechanisms. In recent years, sphingolipid molecules and their regulators have become significant factors in the pathogenesis and multi-drug resistance. Therefore, sphingolipid pathway inhibitors could be used either alone or in combination with existing antifungal drugs for the effective prevention of virulence, and pathogenesis or to kill the pathogenic fungi. In this review, we address the impact of sphingolipid metabolism and its regulators on antifungal drug resistance, as well as how they can be effectively targeted to improve the efficacy of currently available antifungal drugs.