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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI103280-06
Application #
9451801
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
O'Neil, Michael T
Project Start
2012-12-01
Project End
2022-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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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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