Severe malaria due to infection by Plasmodium falciparum is a serious threat to global health with over a million deaths per year. New antimalarial agents are needed due to widespread resistance to existing therapies. A promising antimalarial drug target is the MEP pathway of isoprenoid biosynthesis, which is not found in humans. This pathway is the target of an antimalarial agent, fosmidomycin, which is currently in Phase II clinical trials in combination therapies for malaria. We have used forward genetic screening to identify fosmidomycin-resistant malaria parasites, in order to investigate the genetic mechanisms of fosmidomycin resistance and advance our basic understanding of isoprenoid biology. We have thus identified a new family of metabolic regulators in malaria, the HAD proteins. Our approach consists of two specific aims: (1) Establish the mechanisms of HAD-mediated drug resistance, and (2) Characterize the genetic and metabolic mechanisms that underlie enhanced drug resistance in malaria strains lacking HADs. We will identify P. falciparum genes and pathways that genetically interact with the essential MEP pathway and our strong preliminary results support this approach. Our results will identify molecular biomarkers of fosmidomycin resistance and identify new targets for much needed antimalarial drug development.

Public Health Relevance

(RELEVANCE) Severe malaria due to Plasmodium falciparum kills over a million people a year. Resistance to existing antimalarial drugs has created an urgent need for new drugs. Ongoing antimalarial drug development depends on improving our understanding of the basic biology of this pathogen. Our proposal investigates the biology of isoprenoid biosynthesis in the malaria parasite using an inhibitor of this pathway, fosmidomycin, and will identify new targets for much needed antimalarial drug development.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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O'Neil, Michael T
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Washington University
Schools of Medicine
Saint Louis
United States
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Edwards, Rachel L; Brothers, Robert C; Wang, Xu et al. (2017) MEPicides: potent antimalarial prodrugs targeting isoprenoid biosynthesis. Sci Rep 7:8400
San Jose, GĂ©raldine; Jackson, Emily R; Haymond, Amanda et al. (2016) Structure-Activity Relationships of the MEPicides: N-Acyl and O-Linked Analogs of FR900098 as Inhibitors of Dxr from Mycobacterium tuberculosis and Yersinia pestis. ACS Infect Dis 2:923-935
Price, Kathryn E; Armstrong, Christopher M; Imlay, Leah S et al. (2016) Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD. Sci Rep 6:36777
Edwards, Rachel L; Odom John, Audrey R (2016) Muddled mechanisms: recent progress towards antimalarial target identification. F1000Res 5:2514
Kraft, Thomas E; Heitmeier, Monique R; Putanko, Marina et al. (2016) A Novel Fluorescence Resonance Energy Transfer-Based Screen in High-Throughput Format To Identify Inhibitors of Malarial and Human Glucose Transporters. Antimicrob Agents Chemother 60:7407-7414
Guggisberg, Ann M; Sundararaman, Sesh A; Lanaspa, Miguel et al. (2016) Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin. J Infect Dis 214:1085-91
Suazo, Kiall F; Schaber, Chad; Palsuledesai, Charuta C et al. (2016) Global proteomic analysis of prenylated proteins in Plasmodium falciparum using an alkyne-modified isoprenoid analogue. Sci Rep 6:38615
Guilliams, Martin; Lambrecht, Bart N (2016) Macrophage precursors PLASTed INto alveolar space. Blood 128:2750-2752
Kelly, Megan; Su, Chih-Ying; Schaber, Chad et al. (2015) Malaria parasites produce volatile mosquito attractants. MBio 6:
Kraft, Thomas E; Armstrong, Christopher; Heitmeier, Monique R et al. (2015) The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir. Antimicrob Agents Chemother 59:6203-9

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