Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance

Con Dogovski; Stanley C Xie; Gaetan Burgio; Jess Bridgford; Sachel Mok; James M McCaw; Kesinee Chotivanich; Shannon Kenny; Nina Gnaedig; Judith Straimer; Zbynek Bozdech; David A Fidock; Julie A Simpson; Arjen M Dondorp; Simon Foote; Nectarios Klonis; Leann Tilley

Journal article

Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance

Con Dogovski, Stanley C Xie, Gaetan Burgio, Jess Bridgford, Sachel Mok, James M McCaw, Kesinee Chotivanich, Shannon Kenny, Nina Gnaedig, Judith Straimer, Zbynek Bozdech, David A Fidock, Julie A Simpson, Arjen M Dondorp, Simon Foote, Nectarios Klonis, Leann Tilley

PLOS BIOLOGY | PUBLIC LIBRARY SCIENCE | Published : 2015

DOI: 10.1371/journal.pbio.1002132

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Abstract

Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs) has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. We undertook a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin). We demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. We sh..

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University of Melbourne Researchers

Jessica Bridgford Author Medical Biology (w.e.h.i.)

Leann Tilley Author Biochemistry and Pharmacology

James McCaw Author Mathematics and Statistics

Stanley Xie Author Biochemistry and Pharmacology

Julie Simpson Author Melbourne School of Population and Global Health

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Funding Acknowledgements

This work was supported by the National Health & Medical Research Council of Australia (Grant#541904), the Australia Research Council (Grants: CE0561787 & DP110100624), the Singapore National Medical Council (NMRC/1265/2010), and National Institutes of Health, USA (R01 AI109023, to DAF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.