Plasmodium falciparum choline kinase inhibition leads to a major decrease in phosphatidylethanolamine causing parasite death
MetadataShow full item record
Malaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite’s growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two P. falciparum choline kinase inhibitors both in vitro and in vivo. The compounds present distinct binding modes to the choline/ethanolamine-binding site of P. falciparum choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the P. falciparum choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within P. falciparum, which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting P. falciparum choline kinase.
Serrán-Aguilera , L , Denton , H , Rubio-Ruiz , B , López-Gutiérrez , B , Entrena , A , Izquierdo , L , Smith , T K , Conejo-García , A & Hurtado-Guerrero , R 2016 , ' Plasmodium falciparum choline kinase inhibition leads to a major decrease in phosphatidylethanolamine causing parasite death ' Scientific Reports , vol 6 , 33189 . DOI: 10.1038/srep33189 , 10.1038/srep33189
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
DescriptionThis work was supported by Agencia Aragonesa para la Investigación y Desarrollo (ARAID), Ministerio de Economía y Competitividad (CTQ2013-44367-C2-2-P to R.H.-G.) and Diputación General de Aragón (DGA; B89 to R.H.-G.) and the EU Seventh Framework Programme (2007–2013) under BioStruct-X (grant agreement 283570 and BIOSTRUCTX 5186, to R.H.-G.). T.K.S. was supported by the Wellcome Trust grant 093228 and European Community’s Seventh Framework Programme under grant agreement No. 602773 (Project KINDRED).
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.