Diverse chemical compounds target Plasmodium falciparum plasma membrane lipid homeostasis

Abstract

Lipid homeostasis is essential for the maintenance of life. We previously reported that disruptions of the parasite Na + homeostasis via inhibition of PfATP4 resulted in elevated cholesterol within the parasite plasma membrane as assessed by saponin sensitivity. A large number of compounds have been shown to target the parasite Na + homeostasis. We therefore screened the same collection of 800 compounds to identify chemotypes that disrupted the parasite plasma membrane lipid homeostasis. Here, we show that the compounds disrupting parasite Na + homeostasis also induced saponin sensitivity, an indication of parasite lipid homeostasis disruption. Remarkably, 13 compounds were identified that altered plasma membrane lipid composition independent of Na + homeostasis disruption. Further studies suggest that these compounds target the Plasmodium falciparum Niemann-Pick Type C1-Related (PfNCR1) protein, which is hypothesized to be involved in maintaining plasma membrane lipid composition. PfNCR1, like PfATP4, appears to be targeted by multiple chemotypes with potential for drug discovery.

Comparative transcriptomics and host-specific parasite gene expression profiles inform on drivers of proliferative kidney disease

“…The apparent dominance of myxozoan LDLR-As and PLA1 family members in infected fish kidney tissue is strongly indicative of host cholesterol and acyglycerol exploitation that could be a major contributory factor to PKD pathogenesis. Indeed, recent studies describe several viable pharmacological approaches to interfere with parasite utilisation of host lipids, which may have relevance to the future control of myxozoan parasites [56][57][58] .…”

PfATP4 inhibitors in the Medicines for Malaria Venture Malaria Box and Pathogen Box block the schizont-to-ring transition by inhibiting egress rather than invasion

“…Interestingly, two PfATP4 inhibitors (cipargamin and PA21A050) have been shown to rapidly induce cholesterol accumulation and aberrant clustering of glycosylphosphatidylinositol-anchored proteins in P. falciparum membranes (Das et al, 2016). Moreover, the majority of the putative PfATP4 inhibitors in the Malaria and Pathogen Boxes, including those utilised in this study, have been found to sensitise intra-erythrocytic P. falciparum to the cholesterol-dependent detergent saponin, suggesting that these compounds also cause cholesterol to accumulate in the parasite plasma membrane (Bhatnagar et al, 2019). Given that Apicomplexan GCs appear to respond to lipid-based signals (Bisio et al, 2019;Paul et al, 2020), it is conceivable that the lipid perturbations induced by PfATP4 inhibitors dysregulate or counteract the normal lipid translocation activity of the P4-ATPase domain, thereby hindering its capacity to activate the GC domain.…”