Publication: Imidazolopiperazines kill both rings and dormant rings in wild-type and K13 artemisinin-resistant plasmodium falciparum In Vitro
Issued Date
2018-05-01
Resource Type
ISSN
10986596
00664804
00664804
Other identifier(s)
2-s2.0-85046021909
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Mahidol University
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SCOPUS
Bibliographic Citation
Antimicrobial Agents and Chemotherapy. Vol.62, No.5 (2018)
Suggested Citation
Laurent Dembele, Devendra Kumar Gupta, Michelle Yi Xiu Lim, Xiaoman Ang, Jeremy J. Selva, Kesinee Chotivanich, Chea Nguon, Arjen M. Dondorp, Ghislain M.C. Bonamy, Thierry T. Diagana, Pablo Bifania Imidazolopiperazines kill both rings and dormant rings in wild-type and K13 artemisinin-resistant plasmodium falciparum In Vitro. Antimicrobial Agents and Chemotherapy. Vol.62, No.5 (2018). doi:10.1128/AAC.02235-17 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/46742
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Title
Imidazolopiperazines kill both rings and dormant rings in wild-type and K13 artemisinin-resistant plasmodium falciparum In Vitro
Other Contributor(s)
A-Star, Singapore Immunology Network
Yong Loo Lin School of Medicine
Novartis Institute for Tropical Diseases Pte. Ltd.
Mahidol University
Nuffield Department of Clinical Medicine
Amsterdam UMC - University of Amsterdam
Université des Sciences
National Center for Parasitology, Entomology and Malaria Control
Yong Loo Lin School of Medicine
Novartis Institute for Tropical Diseases Pte. Ltd.
Mahidol University
Nuffield Department of Clinical Medicine
Amsterdam UMC - University of Amsterdam
Université des Sciences
National Center for Parasitology, Entomology and Malaria Control
Abstract
© 2018 Dembele et al. Artemisinin (ART) resistance has spread through Southeast Asia, posing a serious threat to the control and elimination of malaria. ART resistance has been associated with mutations in the Plasmodium falciparum kelch-13 (Pfk13) propeller domain. Phenotypically, ART resistance is defined as delayed parasite clearance in patients due to the reduced susceptibility of early ring-stage parasites to the active metabolite of ART dihydroartemisinin (DHA). Early rings can enter a state of quiescence upon DHA exposure and resume growth in its absence. These quiescent rings are referred to as dormant rings or DHA-pretreated rings (here called dormant rings). The imidazolopiperazines (IPZ) are a novel class of antimalarial drugs that have demonstrated efficacy in early clinical trials. Here, we characterized the stage of action of the IPZ GNF179 and evaluated its activity against rings and dormant rings in wild-type and ART-resistant parasites. Unlike DHA, GNF179 does not induce dormancy. We show that GNF179 is more rapidly cidal against schizonts than against ring and trophozoite stages. However, with 12 h of exposure, the compound effectively kills rings and dormant rings of both susceptible and ART-resistant parasites within 72 h. We further demonstrate that in combination with ART, GNF179 effectively prevents recrudescence of dormant rings, including those bearing pfk13 propeller mutations.