Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum

Benjamin K Dickerman; Brendan Elsworth; Simon A Cobbold; Catherine Q Nie; Malcolm J McConville; Brendan S Crabb; Paul R Gilson

doi:10.1038/srep37502

Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum

Sci Rep. 2016 Nov 22:6:37502. doi: 10.1038/srep37502.

Authors

Benjamin K Dickerman¹, Brendan Elsworth^{1

2}, Simon A Cobbold³, Catherine Q Nie¹, Malcolm J McConville³, Brendan S Crabb^{1

2

3}, Paul R Gilson^{1

2}

Affiliations

¹ Burnet Institute, Melbourne, Victoria, Australia.
² Monash University, Clayton, Victoria, Australia.
³ Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia.

Abstract

Plasmodium parasites are responsible for the devastating disease malaria that affects hundreds of millions of people each year. Blood stage parasites establish new permeability pathways (NPPs) in infected red blood cell membranes to facilitate the uptake of nutrients and removal of parasite waste products. Pharmacological inhibition of the NPPs is expected to lead to nutrient starvation and accumulation of toxic metabolites resulting in parasite death. Here, we have screened a curated library of antimalarial compounds, the MMV Malaria Box, identifying two compounds that inhibit NPP function. Unexpectedly, metabolic profiling suggested that both compounds also inhibit dihydroorotate dehydrogense (DHODH), which is required for pyrimidine synthesis and is a validated drug target in its own right. Expression of yeast DHODH, which bypasses the need for the parasite DHODH, increased parasite resistance to these compounds. These studies identify two potential candidates for therapeutic development that simultaneously target two essential pathways in Plasmodium, NPP and DHODH.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimalarials / analysis
Antimalarials / chemistry
Antimalarials / pharmacology*
Cell Membrane Permeability / drug effects*
Cell Proliferation / drug effects
Dihydroorotate Dehydrogenase
Drug Evaluation, Preclinical
Electron Transport Complex III / metabolism
Enzyme Inhibitors / analysis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Erythrocytes / drug effects
Erythrocytes / parasitology
Genes, Reporter
High-Throughput Screening Assays
Inhibitory Concentration 50
Life Cycle Stages / drug effects*
Luciferases / metabolism
Metabolomics
Oxidoreductases Acting on CH-CH Group Donors / metabolism*
Parasites / drug effects
Parasites / enzymology
Parasites / growth & development
Plasmodium falciparum / drug effects
Plasmodium falciparum / enzymology*
Plasmodium falciparum / growth & development*
Reproducibility of Results
Saccharomyces cerevisiae / metabolism
Sorbitol / pharmacology

Substances

Antimalarials
Dihydroorotate Dehydrogenase
Enzyme Inhibitors
Sorbitol
Luciferases
Oxidoreductases Acting on CH-CH Group Donors
Electron Transport Complex III