Role of Candida albicans phosphate transport in cell wall maintenance and echinocandin tolerance

Boston Children'S Hospital, Boston MA

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Abstract

Project Summary: Role of Candida albicans phosphate transport in cell wall maintenance and echinocandin tolerance The goal of this proposal is to delineate the mechanisms by which the Candida albicans high-affinity phosphate transporter Pho84 enables this fungal pathogen to maintain its cell wall and to withstand drugs of the echinocandin class. C. albicans cells lacking Pho84 are attenuated for virulence in mucosal and systemic murine infection models. Our previous work shows that inhibiting Pho84 with small molecules, including an FDA-approved antiviral agent, potentiates the activity of the echinocandin micafungin. Similarly, null mutants in PHO84 are hypersensitive to micafungin, and to other agents of cell wall stress, while failing to properly activate the cell wall integrity (CWI) signaling pathway. Based on findings of metabolomics experiments, we hypothesize that the mechanism by which C. albicans Pho84 contributes to cell wall biosynthesis and cell wall integrity signaling, is by activating phosphoribosylpyrophosphate (PRPP) synthetase through provision of sufficient cytosolic phosphate. PRPP is a central metabolic intermediate in biosynthesis of cell wall polymer precursors, and PRPP synthetase interacts with cell wall integrity signaling in a model yeast, suggesting a testable model: failure of PRPP synthetase activation deprives cell wall biosynthesis of necessary precursors and diminishes CWI signaling during cell wall stress. The proposed work will test four hypotheses resulting from this model, using methods well established in the laboratory. The overall impact of this proposal is that defining connections between phosphate homeostasis, cell wall biosynthesis and cell wall integrity signaling will contribute novel aspects to our understanding of C. albicans virulence and possibly uncover molecules appropriate for targeting with new antifungal compounds.