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
SCIENTIFIC REPORTS | NATURE PUBLISHING GROUP | Published : 2016
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 dehydroge..View full abstract
This work was supported by the Victorian Operational Infrastructure Support Program received by the Burnet Institute. We acknowledge the Medicines for Malaria Venture (MMV) for providing access to the MMV Malaria Box and the Australian Red Cross Blood Bank for the provision of human blood. B.E. is recipient of an Australian Post Graduate Award. MJM is an NHMRC Principal Research Fellow. We thank Susan Charman for providing DSM1.