title: Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum.
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.
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Dickerman
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia.|Monash University, Clayton, Victoria, Australia.
authors.forename: Brendan
authors.initials: B
authors.lastname: Elsworth
authors.affiliation: Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Cobbold
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia.
authors.forename: Catherine Q
authors.initials: CQ
authors.lastname: Nie
authors.affiliation: Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: McConville
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia.|Monash University, Clayton, Victoria, Australia.|Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Brendan S
authors.initials: BS
authors.lastname: Crabb
authors.affiliation: Burnet Institute, Melbourne, Victoria, Australia.|Monash University, Clayton, Victoria, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gilson
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D000090722:Dihydroorotate Dehydrogenase; D004353:Drug Evaluation, Preclinical; D014450:Electron Transport Complex III / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D020128:Inhibitory Concentration 50; D008018:Life Cycle Stages / Q000187:drug effects*; D008156:Luciferases / Q000378:metabolism; D055432:Metabolomics; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism*; D010271:Parasites / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development*; D015203:Reproducibility of Results; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013012:Sorbitol / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D013012:Sorbitol; D008156:Luciferases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D014450:Electron Transport Complex III