Targeting the lipid metabolic pathways for the treatment of malaria

Abstract

The control and eventual eradication of human malaria is considered one of the most important global public health goals of the 21st Century. Malaria, caused by intraerythrocytic protozoan parasites of the genus Plasmodium, is by far the most lethal and among the most prevalent of the infectious diseases. Four species of Plasmodium (P. falciparum, P. malariae, P. ovale, and P. vivax) are known to be infectious to humans, and more recent cases of infection due to P. knowlesi also have been reported. These species cause approximately 300 million annual cases of clinical malaria resulting in around one million deaths mostly caused by P. falciparum. The rapid emergence of drug-resistant Plasmodium strains has severely reduced the potency of medicines commonly used to treat and block the transmission of malaria and threatens the effectiveness of combination therapy in the field. New drugs that target important parasite functions, which are not the target of current antimalarial drugs, and have the potential to act against multi-drug-resistant Plasmodium strains are urgently needed. Recent studies in P. falciparum have unraveled new metabolic pathways for the synthesis of the parasite phospholipids and fatty acids. The present review summarizes our current understanding of these pathways in Plasmodium development and pathogenesis, and provides an update on the efforts underway to characterize their importance using genetic means and to develop antimalarial therapies targeting lipid metabolic pathways.

Type II Fatty Acid Biosynthesis Is Essential for Plasmodium falciparum Sporozoite Development in the Midgut of Anopheles Mosquitoes

“…These discoveries reversed the long-held dogma that FAS-II was required for blood stages and, by extension, was an excellent drug target for malaria control due to the absence of FAS-II in the human host (15). Nevertheless, pathways of Plasmodium lipid metabolism remain an attractive target for malaria treatment (16,17). Studies on rodent models of malaria demonstrated that FAS-II was only required for liver-stage development.…”

In VivoandIn VitroAntimalarial Properties of Azithromycin-Chloroquine Combinations That Include the Resistance Reversal Agent Amlodipine

“…The possible emergence of resistance underscores a clear need to find alternative regimens. While several promising agents are in the pipeline, the development of antimalarial drugs that are effective, well tolerated, and safe remains a very challenging task (6,27,77,89). In addition, the new paradigm of antimalarial therapies based on the combination of drugs that have additive or preferably synergistic properties raises the threshold for drug discovery even further.…”

Phospholipases during membrane dynamics in malaria parasites

“…Plasmodium generates PL from polar heads, like choline, ethanolamine or serine (S), which are mainly taken up from the serum (reviewed in Ben Mamoun et al, 2010;Déchamps et al, 2010), whereas phosphatidylinositol (PI) is made by the parasite from inositol that is either taken up from the serum or generated de novo from glucose-6-phosphate via inositol-3-phosphate (reviewed in Ramakrishnan et al, 2013). Phosphatidylethanolamine (PE) is synthesized by the parasite via the phosphorylation of ethanolamine obtained from plasma or through decarboxylation of S (Fig.…”