Essential Role for the Phosphatidylinositol 3,5-Bisphosphate Synthesis Complex in Caspofungin Tolerance and Virulence in Candida glabrata

Abstract

Increasing resistance of the human opportunistic fungal pathogen Candida glabrata toward the echinocandin antifungals, which target the cell wall, is a matter of grave clinical concern. Echinocandin resistance in C. glabrata has primarily been associated with mutations in the β-glucan synthase-encoding genes C. glabrata FKS1 (CgFKS1) and CgFKS2. This notwithstanding, the role of the phosphoinositide signaling in antifungal resistance is just beginning to be deciphered. The phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a low-abundance lipid molecule that is pivotal to the intracellular membrane traffic. Here, we demonstrate for the first time that the PI(3,5)P2 kinase CgFab1, along with its activity regulator CgVac7 and the scaffolding protein CgVac14, is required for maintenance of the cell wall chitin content, survival of the cell wall, and caspofungin stress. Further, deletion analyses implicated the PI(3,5)P2 phosphatase CgFig4 in the regulation of PI(3,5)P2 levels and azole and echinocandin tolerance through CgVac14. We also show the localization of the CgFab1 lipid kinase to the vacuole to be independent of the CgVac7, CgVac14, and CgFig4 proteins. Lastly, our data demonstrate an essential requirement for PI(3,5)P2 signaling components, CgFab1, CgVac7, and CgVac14, in the intracellular survival and virulence in C. glabrata. Altogether, our data have yielded key insights into the functions and metabolism of PI(3,5)P2 lipid in the pathogenic yeast C. glabrata. In addition, our data highlight that CgVac7, whose homologs are absent in higher eukaryotes, may represent a promising target for antifungal therapy.

Echinocandin Resistance in Aspergillus fumigatus Has Broad Implications for Membrane Lipid Perturbations That Influence Drug-Target Interactions

“…4 A recent study in C glabrata emphasized the importance of phosphatidylinositol 3,5-bisphosphate, a low abundance lipid molecule, in the maintenance of cell wall chitin, caspofungin tolerance, survival within host cells, and virulence. 26 Another study in C auris , an emerging pathogenic fungus, showed higher abundance of sphingoid bases in its plasma membrane, including higher levels of phytosphingosine compared to C albicans strains. 27 This study also suggests that increased sphingolipid content may be related to increased resistance to antifungals typical of C auris.…”

“…26 Another study in C auris , an emerging pathogenic fungus, showed higher abundance of sphingoid bases in its plasma membrane, including higher levels of phytosphingosine compared to C albicans strains. 27 This study also suggests that increased sphingolipid content may be related to increased resistance to antifungals typical of C auris. The authors mention that these lipids are important for the assembly of membrane platforms containing drug efflux pumps.…”

The effect of antifungal resistance development on the virulence of Candida species

“…It has been previously shown that phosphoinositide signaling pathways have a role in resistance development to azoles by regulating various cellular processes such as protein trafficking, autophagy, cell cycle progression and hyphal morphogenesis (Choudhary et al . 2019 ). Additionally, phosphatidylinositol-4-phosphate is vital for the trafficking of the major multidrug transporter Cdr1, to the plasma membrane (Ghugtyal et al .…”

Candida glabrata Antifungal Resistance and Virulence Factors, a Perfect Pathogenic Combination

“…One study showed that the CgFab1 , CgVac7, and CgVac14 signaling components for phosphatidylinositol 3,5-bisphosphate ( PI (3,5) P2 ) genes are important for biofilm formation, cell survival, and virulence of C. glabrata , since strains with mutations in these genes tend to have a defective cell wall and because the impaired vacuolar functions and biofilm formation observed in vitro was diminished [ 203 ].…”