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Diverse Chemical Compounds Target Plasmodium falciparum Plasma Membrane Lipid Homeostasis
Journal article   Open access

Diverse Chemical Compounds Target Plasmodium falciparum Plasma Membrane Lipid Homeostasis

Suyash Bhatnagar, Sezin Nicklas, Joanne M Morrisey, Daniel E Goldberg and Akhil B Vaidya
ACS infectious diseases, v 5(4), pp 550-558
12 Apr 2019
DOI: https://doi.org/10.1021/acsinfecdis.8b00277
PMID: 30638365
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc6461493View
Accepted (AM) Open

Abstract

Antimalarials - pharmacology Calcium-Transporting ATPases - antagonists & inhibitors Calcium-Transporting ATPases - genetics Calcium-Transporting ATPases - metabolism Cell Membrane - chemistry Cell Membrane - drug effects Cell Membrane - metabolism Erythrocytes - parasitology Homeostasis - drug effects Humans Lipid Metabolism - drug effects Lipids - chemistry Malaria, Falciparum - parasitology Plasmodium falciparum - chemistry Plasmodium falciparum - drug effects Plasmodium falciparum - genetics Plasmodium falciparum - metabolism Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - genetics Protozoan Proteins - metabolism Sodium - metabolism
Lipid homeostasis is essential to 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 screened 800 compounds from the Malaria and Pathogen Boxes 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 the plasma membrane lipid composition independently of the 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 the potential for drug discovery.

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14 citations in Scopus

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Collaboration types
Domestic collaboration
Web of Science research areas
Chemistry, Medicinal
Infectious Diseases
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