Year-end Sale % OFF 
Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0957-z) contains supplementary material, which is available to authorized users.
Highlights
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
Multiplexed fluidic plunger detected time‐dependent rigidification of chloroquine‐treated infected red blood cells (iRBCs) Alteration in RBC deformability after P. falciparum infection and anti-malarial drug treatment was assessed using the multiplexed Fluidic Plunger (MFP) device [21], which measures the deformability of single RBCs based on the pressure required to transit a funnel-shaped microconstriction (Fig. 1)
To evaluate the sensitivity of this system for measuring drug-induced changes in RBC deformability, the deformability of purified P. falciparum 3D7 iRBCs was determined over a range of chloroquine concentrations by measuring the median transit pressure through a microscale funnel (Fig. 2a)
Summary
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. The biophysical character of parasitized cells is a compelling alternative to these conventional biomarkers because parasitized erythrocytes become rigidi‐ fied and this effect is potentiated by anti-malarial compounds, such as chloroquine and artesunate. Owing to the poor success of existing screening methods, there is a need for in vitro screens that align with a common mode of action for anti-malarial compounds in vivo. This type of in vitro method would significantly reduce the burden of animal and human drug trials
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
