Publication Date:
2015-04-16
Description:
Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417027/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417027/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mbengue, Alassane -- Bhattacharjee, Souvik -- Pandharkar, Trupti -- Liu, Haining -- Estiu, Guillermina -- Stahelin, Robert V -- Rizk, Shahir S -- Njimoh, Dieudonne L -- Ryan, Yana -- Chotivanich, Kesinee -- Nguon, Chea -- Ghorbal, Mehdi -- Lopez-Rubio, Jose-Juan -- Pfrender, Michael -- Emrich, Scott -- Mohandas, Narla -- Dondorp, Arjen M -- Wiest, Olaf -- Haldar, Kasturi -- AI039071/AI/NIAID NIH HHS/ -- AI081077/AI/NIAID NIH HHS/ -- DK26263/DK/NIDDK NIH HHS/ -- HL069630/HL/NHLBI NIH HHS/ -- HL078826/HL/NHLBI NIH HHS/ -- R01 DK026263/DK/NIDDK NIH HHS/ -- R01 HL069630/HL/NHLBI NIH HHS/ -- R37 DK026263/DK/NIDDK NIH HHS/ -- England -- Nature. 2015 Apr 30;520(7549):683-7. doi: 10.1038/nature14412. Epub 2015 Apr 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana 46556, USA [2] Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA. ; 1] Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana 46556, USA [2] Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA. ; 1] Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana 46556, USA [2] Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA [3] Department of Biochemistry &Molecular Biology, Indiana University School of Medicine-South Bend, 143 Raclin-Carmichael Hall, 1234 Notre Dame Avenue, South Bend, Indiana 46617, USA. ; 1] Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana 46556, USA [2] Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA [3] Departmen of. Biochemistry and Molecular Biology, Faculty of Science University of Buea, P.O. Box 63 Buea, Southwest region, Cameroon. ; Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400, Thailand. ; National Center for Parasitology, Entomology and Malaria Control, 12302 Phnom Penh, Monivong Blvd, Phnom Penh 12302, Cambodia. ; CNRS 5290/IRD 224/University Montpellier 1&2 ("MiVEGEC"), Montpellier, France. ; Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA. ; Department of Computer Science and Engineering, University of Notre Dame, Notre Dame, Indiana 46556. USA. ; New York Blood Center, New York, New York 10032, USA. ; 1] Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400, Thailand [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN. UK. ; 1] Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, Indiana 46556, USA [2] Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA [3] Laboratory of Computational Chemistry and Drug Design, Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25874676" target="_blank"〉PubMed〈/a〉
Keywords:
Antimalarials/*pharmacology
;
Artemisinins/*pharmacology
;
Drug Resistance/*drug effects/genetics
;
Genome-Wide Association Study
;
Malaria, Falciparum/*drug therapy/*parasitology
;
Models, Molecular
;
Mutation
;
Phosphatidylinositol 3-Kinase/*antagonists & inhibitors/chemistry/metabolism
;
Phosphatidylinositol Phosphates/metabolism
;
Plasmodium falciparum/*drug effects/*enzymology
;
Protozoan Proteins/antagonists & inhibitors/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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