title: Reduced deformability of parasitized red blood cells as a biomarker for anti-malarial drug efficacy.
abstract: BACKGROUND
  Malaria 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.
  
  
  METHODS
  Recently 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.
  
  
  RESULTS
  It 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada. dxy4202@gmail.com.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada. simon.p.duffy@gmail.com.
authors.forename: Simon P
authors.initials: SP
authors.lastname: Duffy
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada. marieeve.myrandlapierre@gmail.com.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Myrand-Lapierre
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada. matthews.kerryn@gmail.com.
authors.forename: Kerryn
authors.initials: K
authors.lastname: Matthews
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada. aline.t.santoso@gmail.com.
authors.forename: Aline Teresa
authors.initials: AT
authors.lastname: Santoso
authors.affiliation: Department of Chemistry, University of British Columbia, Vancouver, BC, Canada. yldu@chem.ubc.ca.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Du
authors.affiliation: Department of Chemistry, University of British Columbia, Vancouver, BC, Canada. ksryan@chem.ubc.ca.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Ryan
authors.affiliation: Department of Mechanical Engineering, University of British Columbia, 2054-6250 Applied Science Lane, Vancouver, BC, V6T 1Z4, Canada. hongma@mech.ubc.ca.|Department of Urologic Science, University of British Columbia, Vancouver, BC, Canada. hongma@mech.ubc.ca.|Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, Canada. hongma@mech.ubc.ca.
authors.forename: Hongshen
authors.initials: H
authors.lastname: Ma
mesh_terms: D000962:Antimalarials / Q000627:therapeutic use*; D015415:Biomarkers; D055592:Biophysical Phenomena; D048430:Cell Shape; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D016903:Drug Monitoring / Q000379:methods*; D004912:Erythrocytes / Q000166:cytology*; D006801:Humans; D056656:Lab-On-A-Chip Devices
chemical_list: D000962:Antimalarials; D015415:Biomarkers