2. Academic Validation
  3. The Plasmodium PI(4)K inhibitor KDU691 selectively inhibits dihydroartemisinin-pretreated Plasmodium falciparum ring-stage parasites

The Plasmodium PI(4)K inhibitor KDU691 selectively inhibits dihydroartemisinin-pretreated Plasmodium falciparum ring-stage parasites

  • Sci Rep. 2017 May 24;7(1):2325. doi: 10.1038/s41598-017-02440-6.
L Dembele 1,  X Ang 1,  M Chavchich 2,  G M C Bonamy 1,  J J Selva 1,  M Yi-Xiu Lim 1,  C Bodenreider 1,  B K S Yeung 1,  F Nosten 3 4,  B M Russell 5,  M D Edstein 2,  J Straimer 6,  D A Fidock 6 7,  T T Diagana 1,  P Bifani 8 9
Affiliations

Affiliations

  • 1 Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore, Singapore.
  • 2 Department of Drug Evaluation, Australian Army Malaria Institute, Brisbane, QLD, 4051, Australia.
  • 3 Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
  • 4 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 5 Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
  • 6 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, 10032, USA.
  • 7 Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA.
  • 8 Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, 138670, Singapore, Singapore. pablo.bifani@gmail.com.
  • 9 Department of Microbiology and Immunology Program, Yong Loo Lin School of Medicine, Life Sciences Institute, National University of Singapore, 119077, Singapore, Singapore. pablo.bifani@gmail.com.
PMID: 28539634 DOI: 10.1038/s41598-017-02440-6
Abstract

Malaria control and elimination are threatened by the emergence and spread of resistance to artemisinin-based combination therapies (ACTs). Experimental evidence suggests that when an artemisinin (ART)-sensitive (K13 wild-type) Plasmodium falciparum strain is exposed to ART derivatives such as dihydroartemisinin (DHA), a small population of the early ring-stage parasites can survive drug treatment by entering cell cycle arrest or dormancy. After drug removal, these parasites can resume growth. Dormancy has been hypothesized to be an adaptive physiological mechanism that has been linked to recrudescence of parasites after monotherapy with ART and, possibly contributes to ART resistance. Here, we evaluate the in vitro drug sensitivity profile of normally-developing P. falciparum ring stages and DHA-pretreated dormant rings (DP-rings) using a panel of antimalarial drugs, including the Plasmodium phosphatidylinositol-4-OH kinase (PI4K)-specific inhibitor KDU691. We report that while KDU691 shows no activity against rings, it is highly inhibitory against DP-rings; a drug effect opposite to that of ART. Moreover, we provide evidence that KDU691 also kills DP-rings of P. falciparum ART-resistant strains expressing mutant K13.

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