Plasmodium falciparum is a protozoan pathogen that causes the deadliest form of malaria. Malaria has a tremendous impact on human health worldwide, causing nearly one million deaths per year. New therapies are urgently needed to treat this disease, due to widespread chloroquine resistance and emerging resistance to artemisinins. P. falciparum possesses an essential metabolic pathway, non-mevalonate isoprenoid biosynthesis (the MEP pathway), which is not present in humans. This pathway is a particularly enticing antimalarial drug target because it is shared by other important human pathogens, including Gram-negative bacteria and Mycobacterium tuberculosis. The long-term goal is to understand why isoprenoids are essential in malaria parasites. Fosmidomycin is a validated inhibitor of the MEP pathway and is currently in Phase II clinical trials of combination therapy to treat malaria. In preliminary studies, a collection of fosmidomycin-resistant malaria parasites have been developed that not only lack mutations in the known targets of this drug but also continue to grow even when isoprenoid biosynthesis is inhibited. These fosmidomycin-resistant strains presumably survive through genetic changes in a """"""""rescue pathway."""""""" The objective of this proposal is to determine the biochemical and genetic mechanisms by which these parasites have become resistant. The rationale for these studies is that identification of the genes and pathways that genetically interact with fosmidomycin will inform the regulation and downstream biology of isoprenoid biosynthesis in P. falciparum. Understanding how fosmidomycin-resistant malaria strains survive, despite inhibition of isoprenoid biosynthesis, will elucidate why isoprenoids are typically essential. This approach takes advantage of a pathogen-specific biochemical pathway and a potent chemical inhibitor of isoprenoid biosynthesis that is already in clinical trials. Supported by strong preliminary data that indicate that this strategy wll be successful, the objectives will be met through three specific aims: 1) metabolic analysis of MEP metabolism and protein prenylation (an important function of isoprenoid biosynthesis) in fosmidomycin-resistant malaria parasites;2) genetic analysis of fosmidomycin-resistant malaria parasites through next-generation sequencing strategies;and 3) identification of the genetic changes that confer fosmidomycin resistance, by recapitulating candidate resistance mutations in sensitive wild-type parasite lines. This approach is innovative, since it uses genetic characterization of drug-resistant malaria parasites not only for drug target validation, but also o expand the fundamental biological understanding of an essential metabolic pathway. The proposed research is significant, because it will identify diagnostic biomarkers of fosmidomycin resistance, improve functional annotation of """"""""hypothetical"""""""" genes in the P. falciparum genome, and identify new targets for much-needed antimalarial drug development.

Public Health Relevance

This research is highly relevant to public health because severe malaria due to P. falciparum causes nearly one million deaths per year, and ongoing antimalarial drug development depends on improving knowledge of the basic biology of P. falciparum. Our proposal will improve understanding of an essential metabolic pathway in the malaria parasite. These results will identify new drug targets that may lead to future development of novel antimalarial therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Rogers, Martin J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
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

Showing the most recent 10 out of 19 publications