Reduced deformability of parasitized red blood cells as a biomarker for anti-malarial drug efficacy

Malaria Journal

Research

Yi-Ling Du¹  Katherine S. Ryan¹  Aline Teresa Santoso²  Simon P. Duffy²  Marie-Eve Myrand-Lapierre²  Kerryn Matthews²  Xiaoyan Deng²  Hongshen Ma³ 

[1] Department of Chemistry, University of British Columbia, Vancouver, BC, Canada;Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, V6T 1Z4, Vancouver, BC, Canada;Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, V6T 1Z4, Vancouver, BC, Canada;Department of Urologic Science, University of British Columbia, Vancouver, BC, Canada;Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada;

关键词: Cell deformability;    Malaria;    Plasmodium falciparum;    Drug screening;    Biomarkers;   

DOI  :  10.1186/s12936-015-0957-z

 received in 2015-08-19, accepted in 2015-10-21,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMalaria remains a challenging and fatal infectious disease in developing nations and the urgency for the development of new drugs is even greater due to the rapid spread of anti-malarial drug resistance. While numerous parasite genetic, protein and metabolite biomarkers have been proposed for testing emerging anti-malarial compounds, they do not universally correspond with drug efficacy. The biophysical character of parasitized cells is a compelling alternative to these conventional biomarkers because parasitized erythrocytes become specifically rigidified and this effect is potentiated by anti-malarial compounds, such as chloroquine and artesunate. This biophysical biomarker is particularly relevant because of the mechanistic link between cell deformability and enhanced splenic clearance of parasitized erythrocytes.MethodsRecently a microfluidic mechanism, called the multiplexed fluidic plunger that provides sensitive and rapid measurement of single red blood cell deformability was developed. Here it was systematically used to evaluate the deformability changes of late-stage trophozoite-infected red blood cells (iRBCs) after treatment with established clinical and pre-clinical anti-malarial compounds.ResultsIt was found that rapid and specific iRBC rigidification was a universal outcome of all but one of these drug treatments. The greatest change in iRBC rigidity was observed for (+)-SJ733 and NITD246 spiroindolone compounds, which target the Plasmodium falciparum cation-transporting ATPase ATP4. As a proof-of-principle, compounds of the bisindole alkaloid class were screened, where cladoniamide A was identified based on rigidification of iRBCs and was found to have previously unreported anti-malarial activity with an IC50 lower than chloroquine.ConclusionThese results demonstrate that rigidification of iRBCs may be used as a biomarker for anti-malarial drug efficacy, as well as for new drug screening. The novel anti-malarial properties of cladoniamide A were revealed in a proof-of-principle drug screen.

【 授权许可】

CC BY   
© Deng et al. 2015