In the malaria parasite Plasmodium falciparum, the synthesis of isoprenoids from glycolytic intermediates is essential for parasite survival. The antibiotic fosmidomycin (FSM) inhibits isoprenoid synthesis and is an effective antimalarial. In FSM-resistant P. falciparum, we identify a loss-of-function mutation in HAD2 (PF3D7_1226300) as causative for resistance. Enzymatic characterization shows that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, functions as a purine phosphatase. Harnessing a growth defect in HAD2-mutant parasites, we select for suppression of HAD2-mediated FSM resistance and uncover hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase (PFK9, PF3D7_0915400). Metabolic profiling demonstrates that FSM resistance is achieved via increased steady-state levels of MEP pathway and glycolytic intermediates and confirms reduced PFK9 function in the suppressed strains. We thus identify HAD2 as a novel and essential mediator of malaria parasite metabolism and drug sensitivity. Our studies inform the biological functions of evolutionarily conserved family of metabolic regulators, the HAD proteins, and reveal a previously undescribed strategy for glycolytic regulation in cells.

Drug resistance reveals a new family of metabolic regulators in malaria parasites

254th National Meeting (2017)

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