Please use this identifier to cite or link to this item: https://doi.org/10.1128/AAC.02235-17
Title: Imidazolopiperazines kill both rings and dormant rings in wild-type and K13 artemisinin-resistant plasmodium falciparum In Vitro
Authors: Dembele, L
Gupta, D.K
Lim, M.Y.-X
Ang, X
Selva, J.J
Chotivanich, K
Nguon, C
Dondorp, A.M
Bonamy, G.M.C
Diagana, T.T 
Bifania, P
Keywords: antimalarial agent
dihydroartemisinin
dimethyl sulfoxide
gnf 179
imidazole derivative
kdu 691
kelch 13 protein
membrane protein
microorganism protein
piperazine derivative
unclassified drug
antimalarial agent
artemisinin derivative
imidazole derivative
piperazine derivative
protozoal protein
antimalarial activity
antimalarial drug resistance
antimalarial drug susceptibility
apoptosis
Article
cell viability
combination drug therapy
controlled study
development
dormancy
drug efficacy
drug mechanism
drug potentiation
erythrocyte
genotype
IC50
in vitro study
nonhuman
Plasmodium falciparum
priority journal
recrudescence
schizont
trophozoite
wild type
drug effect
drug sensitivity
genetics
metabolism
Plasmodium falciparum
Antimalarials
Artemisinins
Imidazoles
Parasitic Sensitivity Tests
Piperazines
Plasmodium falciparum
Protozoan Proteins
Schizonts
Trophozoites
Issue Date: 2018
Publisher: American Society for Microbiology
Citation: Dembele, L, Gupta, D.K, Lim, M.Y.-X, Ang, X, Selva, J.J, Chotivanich, K, Nguon, C, Dondorp, A.M, Bonamy, G.M.C, Diagana, T.T, Bifania, P (2018). Imidazolopiperazines kill both rings and dormant rings in wild-type and K13 artemisinin-resistant plasmodium falciparum In Vitro. Antimicrobial Agents and Chemotherapy 62 (5) : e02235-17. ScholarBank@NUS Repository. https://doi.org/10.1128/AAC.02235-17
Abstract: 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. © 2018 Dembele et al.
Source Title: Antimicrobial Agents and Chemotherapy
URI: https://scholarbank.nus.edu.sg/handle/10635/175115
ISSN: 0066-4804
DOI: 10.1128/AAC.02235-17
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