PT  - JOURNAL ARTICLE
AU  - Ann M. Guggisberg
AU  - Philip M. Frasse
AU  - Andrew J. Jezewski
AU  - Natasha M. Kafai
AU  - Aakash Y. Gandhi
AU  - Samuel J. Erlinger
AU  - Audrey R. Odom John
TI  - Suppression of drug resistance reveals a genetic mechanism of metabolic plasticity in malaria parasites
AID  - 10.1101/155523
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 155523
4099  - http://biorxiv.org/content/early/2018/06/18/155523.short
4100  - http://biorxiv.org/content/early/2018/06/18/155523.full
AB  - 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 identify a loss-of-function mutation in HAD2 (PF3D7_1226300) as necessary for FSM resistance. Enzymatic characterization reveals that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we select for suppression of HAD2-mediated FSM resistance and uncover hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase (PFK9). 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 identify HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncover PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our study 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 are urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our study 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 uncover 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 to antimalarials.