Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for <named-content content-type="genus-species">Candida albicans</named-content> Cell Wall Maintenance

ABSTRACT The Candida albicans high-affinity phosphate transporter Pho84 is required for normal Target of Rapamycin (TOR) signaling, oxidative stress resistance, and virulence of this fungal pathogen. It also contributes to C. albicans’ tolerance of two antifungal drug classes, polyenes and echinocan...

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Autores principales:	Ning-Ning Liu, Maikel Acosta-Zaldívar, Wanjun Qi, Joann Diray-Arce, Louise A. Walker, Theodore J. Kottom, Rachel Kelly, Min Yuan, John M. Asara, Jessica Ann Lasky-Su, Ofer Levy, Andrew H. Limper, Neil A. R. Gow, Julia R. Köhler
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Candida albicans Pho84 antifungal agents cell wall chitin synthase glucan synthase Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/dd3ae8e11a964f948c0d20db254e5bb3
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spelling	oai:doaj.org-article:dd3ae8e11a964f948c0d20db254e5bb32021-11-15T15:57:01ZPhosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for <named-content content-type="genus-species">Candida albicans</named-content> Cell Wall Maintenance10.1128/mBio.03225-192150-7511https://doaj.org/article/dd3ae8e11a964f948c0d20db254e5bb32020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03225-19https://doaj.org/toc/2150-7511ABSTRACT The Candida albicans high-affinity phosphate transporter Pho84 is required for normal Target of Rapamycin (TOR) signaling, oxidative stress resistance, and virulence of this fungal pathogen. It also contributes to C. albicans’ tolerance of two antifungal drug classes, polyenes and echinocandins. Echinocandins inhibit biosynthesis of a major cell wall component, beta-1,3-glucan. Cells lacking Pho84 were hypersensitive to other forms of cell wall stress beyond echinocandin exposure, while their cell wall integrity signaling response was weak. Metabolomics experiments showed that levels of phosphoric intermediates, including nucleotides like ATP and nucleotide sugars, were low in pho84 mutant compared to wild-type cells recovering from phosphate starvation. Nonphosphoric precursors like nucleobases and nucleosides were elevated. Outer cell wall phosphomannan biosynthesis requires a nucleotide sugar, GDP-mannose. The nucleotide sugar UDP-glucose is the substrate of enzymes that synthesize two major structural cell wall polysaccharides, beta-1,3- and beta-1,6-glucan. Another nucleotide sugar, UDP-N-acetylglucosamine, is the substrate of chitin synthases which produce a stabilizing component of the intercellular septum and of lateral cell walls. Lack of Pho84 activity, and phosphate starvation, potentiated pharmacological or genetic perturbation of these enzymes. We posit that low substrate concentrations of beta-d-glucan- and chitin synthases, together with pharmacologic inhibition of their activity, diminish enzymatic reaction rates as well as the yield of their cell wall-stabilizing products. Phosphate import is not conserved between fungal and human cells, and humans do not synthesize beta-d-glucans or chitin. Hence, inhibiting these processes simultaneously could yield potent antifungal effects with low toxicity to humans. IMPORTANCE Candida species cause hundreds of thousands of invasive infections with high mortality each year. Developing novel antifungal agents is challenging due to the many similarities between fungal and human cells. Maintaining phosphate balance is essential for all organisms but is achieved completely differently by fungi and humans. A protein that imports phosphate into fungal cells, Pho84, is not present in humans and is required for normal cell wall stress resistance and cell wall integrity signaling in C. albicans. Nucleotide sugars, which are phosphate-containing building block molecules for construction of the cell wall, are diminished in cells lacking Pho84. Cell wall-constructing enzymes may be slowed by lack of these building blocks, in addition to being inhibited by drugs. Combined targeting of Pho84 and cell wall-constructing enzymes may provide a strategy for antifungal therapy by which two sequential steps of cell wall maintenance are blocked for greater potency.Ning-Ning LiuMaikel Acosta-ZaldívarWanjun QiJoann Diray-ArceLouise A. WalkerTheodore J. KottomRachel KellyMin YuanJohn M. AsaraJessica Ann Lasky-SuOfer LevyAndrew H. LimperNeil A. R. GowJulia R. KöhlerAmerican Society for MicrobiologyarticleCandida albicansPho84antifungal agentscell wallchitin synthaseglucan synthaseMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans Pho84 antifungal agents cell wall chitin synthase glucan synthase Microbiology QR1-502
spellingShingle	Candida albicans Pho84 antifungal agents cell wall chitin synthase glucan synthase Microbiology QR1-502 Ning-Ning Liu Maikel Acosta-Zaldívar Wanjun Qi Joann Diray-Arce Louise A. Walker Theodore J. Kottom Rachel Kelly Min Yuan John M. Asara Jessica Ann Lasky-Su Ofer Levy Andrew H. Limper Neil A. R. Gow Julia R. Köhler Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for <named-content content-type="genus-species">Candida albicans</named-content> Cell Wall Maintenance
description	ABSTRACT The Candida albicans high-affinity phosphate transporter Pho84 is required for normal Target of Rapamycin (TOR) signaling, oxidative stress resistance, and virulence of this fungal pathogen. It also contributes to C. albicans’ tolerance of two antifungal drug classes, polyenes and echinocandins. Echinocandins inhibit biosynthesis of a major cell wall component, beta-1,3-glucan. Cells lacking Pho84 were hypersensitive to other forms of cell wall stress beyond echinocandin exposure, while their cell wall integrity signaling response was weak. Metabolomics experiments showed that levels of phosphoric intermediates, including nucleotides like ATP and nucleotide sugars, were low in pho84 mutant compared to wild-type cells recovering from phosphate starvation. Nonphosphoric precursors like nucleobases and nucleosides were elevated. Outer cell wall phosphomannan biosynthesis requires a nucleotide sugar, GDP-mannose. The nucleotide sugar UDP-glucose is the substrate of enzymes that synthesize two major structural cell wall polysaccharides, beta-1,3- and beta-1,6-glucan. Another nucleotide sugar, UDP-N-acetylglucosamine, is the substrate of chitin synthases which produce a stabilizing component of the intercellular septum and of lateral cell walls. Lack of Pho84 activity, and phosphate starvation, potentiated pharmacological or genetic perturbation of these enzymes. We posit that low substrate concentrations of beta-d-glucan- and chitin synthases, together with pharmacologic inhibition of their activity, diminish enzymatic reaction rates as well as the yield of their cell wall-stabilizing products. Phosphate import is not conserved between fungal and human cells, and humans do not synthesize beta-d-glucans or chitin. Hence, inhibiting these processes simultaneously could yield potent antifungal effects with low toxicity to humans. IMPORTANCE Candida species cause hundreds of thousands of invasive infections with high mortality each year. Developing novel antifungal agents is challenging due to the many similarities between fungal and human cells. Maintaining phosphate balance is essential for all organisms but is achieved completely differently by fungi and humans. A protein that imports phosphate into fungal cells, Pho84, is not present in humans and is required for normal cell wall stress resistance and cell wall integrity signaling in C. albicans. Nucleotide sugars, which are phosphate-containing building block molecules for construction of the cell wall, are diminished in cells lacking Pho84. Cell wall-constructing enzymes may be slowed by lack of these building blocks, in addition to being inhibited by drugs. Combined targeting of Pho84 and cell wall-constructing enzymes may provide a strategy for antifungal therapy by which two sequential steps of cell wall maintenance are blocked for greater potency.
format	article
author	Ning-Ning Liu Maikel Acosta-Zaldívar Wanjun Qi Joann Diray-Arce Louise A. Walker Theodore J. Kottom Rachel Kelly Min Yuan John M. Asara Jessica Ann Lasky-Su Ofer Levy Andrew H. Limper Neil A. R. Gow Julia R. Köhler
author_facet	Ning-Ning Liu Maikel Acosta-Zaldívar Wanjun Qi Joann Diray-Arce Louise A. Walker Theodore J. Kottom Rachel Kelly Min Yuan John M. Asara Jessica Ann Lasky-Su Ofer Levy Andrew H. Limper Neil A. R. Gow Julia R. Köhler
author_sort	Ning-Ning Liu
title	Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for <named-content content-type="genus-species">Candida albicans</named-content> Cell Wall Maintenance
title_short	Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for <named-content content-type="genus-species">Candida albicans</named-content> Cell Wall Maintenance
title_full	Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for <named-content content-type="genus-species">Candida albicans</named-content> Cell Wall Maintenance
title_fullStr	Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for <named-content content-type="genus-species">Candida albicans</named-content> Cell Wall Maintenance
title_full_unstemmed	Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for <named-content content-type="genus-species">Candida albicans</named-content> Cell Wall Maintenance
title_sort	phosphoric metabolites link phosphate import and polysaccharide biosynthesis for <named-content content-type="genus-species">candida albicans</named-content> cell wall maintenance
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/dd3ae8e11a964f948c0d20db254e5bb3
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Phosphoric Metabolites Link Phosphate Import and Polysaccharide Biosynthesis for <named-content content-type="genus-species">Candida albicans</named-content> Cell Wall Maintenance

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