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Choudhary, D.K. and Bhakt, Priyanka and Kaur, Rupinder (2019) An essential role for the PI(3,5)P2 synthesis complex in caspofungin tolerance and virulence in Candida glabrata. Antimicrobial Agents and Chemotherapy, 63 (8). e00886-19. ISSN 0066-4804

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Abstract

Increasing resistance of the human opportunistic fungal pathogen Candida glabrata towards 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 CgFKS1 and CgFKS2 This notwithstanding, role of the phosphoinositide signalling in antifungal resistance is just beginning to be deciphered. The phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] is a low-abundant 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, and 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 CgVac7, CgVac14 and CgFig4 protein. Lastly, our data demonstrate an essential requirement for PI(3,5)P2 signalling 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.

Item Type: Article
Depositing User: Dr P Divakar
Date Deposited: 03 Jun 2019 13:46
Last Modified: 26 Oct 2019 12:10
URI: http://cdfd.sciencecentral.in/id/eprint/904

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