The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides

ABSTRACT Plasmodium parasites rely heavily on glycolysis for ATP production and for precursors for essential anabolic pathways, such as the methylerythritol phosphate (MEP) pathway. Here, we show that mutations in the Plasmodium falciparum glycolytic enzyme, phosphofructokinase (PfPFK9), are associa...

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Autores principales:	Gillian M. Fisher, Simon A. Cobbold, Andrew Jezewski, Emma F. Carpenter, Megan Arnold, Annie N. Cowell, Erick T. Tjhin, Kevin J. Saliba, Tina S. Skinner-Adams, Marcus C. S. Lee, Audrey Odom John, Elizabeth A. Winzeler, Malcolm J. McConville, Sally-Ann Poulsen, Katherine T. Andrews
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Plasmodium falciparum drug resistance mechanisms drug targets glycolysis metabolic regulation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/610827e8ff5a4ac08e02462e0f5e26af
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spelling	oai:doaj.org-article:610827e8ff5a4ac08e02462e0f5e26af2021-11-15T15:55:43ZThe Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides10.1128/mBio.02842-202150-7511https://doaj.org/article/610827e8ff5a4ac08e02462e0f5e26af2020-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02842-20https://doaj.org/toc/2150-7511ABSTRACT Plasmodium parasites rely heavily on glycolysis for ATP production and for precursors for essential anabolic pathways, such as the methylerythritol phosphate (MEP) pathway. Here, we show that mutations in the Plasmodium falciparum glycolytic enzyme, phosphofructokinase (PfPFK9), are associated with in vitro resistance to a primary sulfonamide glycoside (PS-3). Flux through the upper glycolysis pathway was significantly reduced in PS-3-resistant parasites, which was associated with reduced ATP levels but increased flux into the pentose phosphate pathway. PS-3 may directly or indirectly target enzymes in these pathways, as PS-3-treated parasites had elevated levels of glycolytic and tricarboxylic acid (TCA) cycle intermediates. PS-3 resistance also led to reduced MEP pathway intermediates, and PS-3-resistant parasites were hypersensitive to the MEP pathway inhibitor, fosmidomycin. Overall, this study suggests that PS-3 disrupts core pathways in central carbon metabolism, which is compensated for by mutations in PfPFK9, highlighting a novel metabolic drug resistance mechanism in P. falciparum. IMPORTANCE Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue, causing 405,000 deaths and 228 million cases in 2018. Understanding key metabolic processes in malaria parasites is critical to the development of new drugs to combat this major infectious disease. The Plasmodium glycolytic pathway is essential to the malaria parasite, providing energy for growth and replication and supplying important biomolecules for other essential Plasmodium anabolic pathways. Despite this overreliance on glycolysis, no current drugs target glycolysis, and there is a paucity of information on critical glycolysis targets. Our work addresses this unmet need, providing new mechanistic insights into this key pathway.Gillian M. FisherSimon A. CobboldAndrew JezewskiEmma F. CarpenterMegan ArnoldAnnie N. CowellErick T. TjhinKevin J. SalibaTina S. Skinner-AdamsMarcus C. S. LeeAudrey Odom JohnElizabeth A. WinzelerMalcolm J. McConvilleSally-Ann PoulsenKatherine T. AndrewsAmerican Society for MicrobiologyarticlePlasmodium falciparumdrug resistance mechanismsdrug targetsglycolysismetabolic regulationMicrobiologyQR1-502ENmBio, Vol 11, Iss 6 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Plasmodium falciparum drug resistance mechanisms drug targets glycolysis metabolic regulation Microbiology QR1-502
spellingShingle	Plasmodium falciparum drug resistance mechanisms drug targets glycolysis metabolic regulation Microbiology QR1-502 Gillian M. Fisher Simon A. Cobbold Andrew Jezewski Emma F. Carpenter Megan Arnold Annie N. Cowell Erick T. Tjhin Kevin J. Saliba Tina S. Skinner-Adams Marcus C. S. Lee Audrey Odom John Elizabeth A. Winzeler Malcolm J. McConville Sally-Ann Poulsen Katherine T. Andrews The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides
description	ABSTRACT Plasmodium parasites rely heavily on glycolysis for ATP production and for precursors for essential anabolic pathways, such as the methylerythritol phosphate (MEP) pathway. Here, we show that mutations in the Plasmodium falciparum glycolytic enzyme, phosphofructokinase (PfPFK9), are associated with in vitro resistance to a primary sulfonamide glycoside (PS-3). Flux through the upper glycolysis pathway was significantly reduced in PS-3-resistant parasites, which was associated with reduced ATP levels but increased flux into the pentose phosphate pathway. PS-3 may directly or indirectly target enzymes in these pathways, as PS-3-treated parasites had elevated levels of glycolytic and tricarboxylic acid (TCA) cycle intermediates. PS-3 resistance also led to reduced MEP pathway intermediates, and PS-3-resistant parasites were hypersensitive to the MEP pathway inhibitor, fosmidomycin. Overall, this study suggests that PS-3 disrupts core pathways in central carbon metabolism, which is compensated for by mutations in PfPFK9, highlighting a novel metabolic drug resistance mechanism in P. falciparum. IMPORTANCE Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue, causing 405,000 deaths and 228 million cases in 2018. Understanding key metabolic processes in malaria parasites is critical to the development of new drugs to combat this major infectious disease. The Plasmodium glycolytic pathway is essential to the malaria parasite, providing energy for growth and replication and supplying important biomolecules for other essential Plasmodium anabolic pathways. Despite this overreliance on glycolysis, no current drugs target glycolysis, and there is a paucity of information on critical glycolysis targets. Our work addresses this unmet need, providing new mechanistic insights into this key pathway.
format	article
author	Gillian M. Fisher Simon A. Cobbold Andrew Jezewski Emma F. Carpenter Megan Arnold Annie N. Cowell Erick T. Tjhin Kevin J. Saliba Tina S. Skinner-Adams Marcus C. S. Lee Audrey Odom John Elizabeth A. Winzeler Malcolm J. McConville Sally-Ann Poulsen Katherine T. Andrews
author_facet	Gillian M. Fisher Simon A. Cobbold Andrew Jezewski Emma F. Carpenter Megan Arnold Annie N. Cowell Erick T. Tjhin Kevin J. Saliba Tina S. Skinner-Adams Marcus C. S. Lee Audrey Odom John Elizabeth A. Winzeler Malcolm J. McConville Sally-Ann Poulsen Katherine T. Andrews
author_sort	Gillian M. Fisher
title	The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides
title_short	The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides
title_full	The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides
title_fullStr	The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides
title_full_unstemmed	The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides
title_sort	key glycolytic enzyme phosphofructokinase is involved in resistance to antiplasmodial glycosides
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/610827e8ff5a4ac08e02462e0f5e26af
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The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides

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