Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites

ABSTRACT In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300...

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Autores principales:	Ann M. Guggisberg, Philip M. Frasse, Andrew J. Jezewski, Natasha M. Kafai, Aakash Y. Gandhi, Samuel J. Erlinger, Audrey R. Odom John
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Plasmodium antimalarial agents drug resistance mechanisms fosmidomycin glycolysis isoprenoids Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0d2cdb80aa98443e8071149bc2d037ca
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spelling	oai:doaj.org-article:0d2cdb80aa98443e8071149bc2d037ca2021-11-15T15:52:19ZSuppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites10.1128/mBio.01193-182150-7511https://doaj.org/article/0d2cdb80aa98443e8071149bc2d037ca2018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01193-18https://doaj.org/toc/2150-7511ABSTRACT In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation. IMPORTANCE Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials.Ann M. GuggisbergPhilip M. FrasseAndrew J. JezewskiNatasha M. KafaiAakash Y. GandhiSamuel J. ErlingerAudrey R. Odom JohnAmerican Society for MicrobiologyarticlePlasmodiumantimalarial agentsdrug resistance mechanismsfosmidomycinglycolysisisoprenoidsMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Plasmodium antimalarial agents drug resistance mechanisms fosmidomycin glycolysis isoprenoids Microbiology QR1-502
spellingShingle	Plasmodium antimalarial agents drug resistance mechanisms fosmidomycin glycolysis isoprenoids Microbiology QR1-502 Ann M. Guggisberg Philip M. Frasse Andrew J. Jezewski Natasha M. Kafai Aakash Y. Gandhi Samuel J. Erlinger Audrey R. Odom John Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites
description	ABSTRACT In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation. IMPORTANCE Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials.
format	article
author	Ann M. Guggisberg Philip M. Frasse Andrew J. Jezewski Natasha M. Kafai Aakash Y. Gandhi Samuel J. Erlinger Audrey R. Odom John
author_facet	Ann M. Guggisberg Philip M. Frasse Andrew J. Jezewski Natasha M. Kafai Aakash Y. Gandhi Samuel J. Erlinger Audrey R. Odom John
author_sort	Ann M. Guggisberg
title	Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites
title_short	Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites
title_full	Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites
title_fullStr	Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites
title_full_unstemmed	Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites
title_sort	suppression of drug resistance reveals a genetic mechanism of metabolic plasticity in malaria parasites
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/0d2cdb80aa98443e8071149bc2d037ca
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Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites

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