5 research outputs found
Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model
Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent
Effect of fosmidomycin on metabolic and transcript profiles of the methylerythritol phosphate pathway in Plasmodium falciparum
Effect of fosmidomycin on metabolic and transcript profiles of the methylerythritol phosphate pathway in Plasmodium falciparum
In Plasmodium falciparum , the formation of isopentenyl diphosphate
and dimethylallyl diphosphate, central intermediates in the
biosynthesis of isoprenoids, occurs via the methylerythritol phosphate
(MEP) pathway. Fosmidomycin is a specific inhibitor of the second
enzyme of the MEP pathway, 1-deoxy-D-xylulose-5-phosphate
reductoisomerase. We analyzed the effect of fosmidomycin on the levels
of each intermediate and its metabolic requirement for the isoprenoid
biosynthesis, such as dolichols and ubiquinones, throughout the
intraerythrocytic cycle of P. falciparum. The steady-state RNA levels
of the MEP pathway-associated genes were quantified by real-time
polymerase chain reaction and correlated with the related metabolite
levels. Our results indicate that MEP pathway metabolite peak precede
maximum transcript abundance during the intraerythrocytic cycle.
Fosmidomycin-treatment resulted in a decrease of the intermediate
levels in the MEP pathway as well as in ubiquinone and dolichol
biosynthesis. The MEP pathway associated transcripts were modestly
altered by the drug, indicating that the parasite is not strongly
responsive at the transcriptional level. This is the first study that
compares the effect of fosmidomycin on the metabolic and transcript
profiles in P. falciparum, which has only the MEP pathway for
isoprenoid biosynthesis