Sphingolipids: Regulators of azole drug resistance and fungal pathogenicity

Abstract

In recent years, the role of sphingolipids in pathogenic fungi, in terms of pathogenicity and resistance to azole drugs, has been a rapidly growing field. This review describes evidence about the roles of sphingolipids in azole resistance and fungal virulence. Sphingolipids can serve as signaling molecules that contribute to azole resistance through modulation of the expression of drug efflux pumps. They also contribute to azole resistance by participating in various microbial pathways such as the unfolded protein response (UPR), pH-responsive Rim pathway, and pleiotropic drug resistance (PDR) pathway. In addition, sphingolipid signaling and eisosomes also coordinately regulate sphingolipid biosynthesis in response to azole-induced membrane stress. Sphingolipids are important for fungal virulence, playing roles during growth in hosts under stressful conditions, maintenance of cell wall integrity, biofilm formation, and production of various virulence factors. Finally, we discuss the possibility of exploiting fungal sphingolipids for the development of new therapeutic strategies to treat infections caused by pathogenic fungi.

Acidic/Alkaline Stress Mediates Responses to Azole Drugs and Oxidative Stress in Aspergillus fumigatus

“…Recent studies showed that evolution of fungal azole drug resistance is associated with genetic stability ( 19 – 21 ). Additionally, previous studies reported that sphingolipid metabolism is closely related to the regulation of azole sensitivity ( 5 , 22 ). Taken as a whole, the sensitivity of A. fumigatus to azole drugs under alkaline conditions may be related to a change of genetic stability and cell membrane lipid composition.…”

“…The degradative and microbicidal microenvironment of this organelle is associated with low pH, the generation of reactive oxygen species, and the presence of defensins and hydrolytic enzymes ( 3 , 4 ). Moreover, antifungal drugs such as azoles are often used to exert stress on the cell membrane of A. fumigatus ( 5 ). Thus, human phagocytic cells combat A. fumigatus infections by killing this fungus with a potent mixture of these stresses.…”

“…As shown in Table S1 in the supplemental material, microarray experiments revealed significant numbers of genes related to lipid metabolism and amino acid metabolism. Previous studies reported that amino acid metabolism and lipid metabolism, such as sphingolipid metabolism, are closely related to the regulation of azole sensitivity ( 5 , 13 – 18 ). Therefore, we speculate that the increased sensitivity of A. fumigatus to azole drugs under acidic conditions may be related to a change of cell membrane lipid composition.…”

Unmasking of CgYor1-Dependent Azole Resistance Mediated by Target of Rapamycin (TOR) and Calcineurin Signaling in Candida glabrata

“…The sphingolipid profiles of the WT and Cg yor1 Δ strains were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based analysis. Interestingly, the phytoceramide (PCer) level, which is the most abundant ceramide and can influence azole resistance ( 57 ), was significantly increased in the Cg yor1 Δ mutant ( Fig. 5f ).…”

Molecular Mechanisms of Antifungal Resistance in Mucormycosis

“…Fluconazole is the most commonly prescribed azole for fungal infection prevention and treatment. However, azole resistance has emerged in a number of species, which is a new concern that is generating therapeutic failures [ 5 ].…”