The Spiroindolone KAE609 Does Not Induce Dormant Ring Stages in Plasmodium falciparum Parasites.
In vitro drug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage in Plasmodium falciparum This response has been proposed to play a role in the recrudescence of P. falciparum infections following monotherapy with artesunate and may contribute to the development of artemisinin resistance in P. falciparum malaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest of P. falciparum parasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage of P. falciparum and prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistant P. falciparum malaria.
Australian Army Malaria Institute, Enoggera, Brisbane, QLD, Australia Marina.Chavchich@defence.gov.au.
Marina
M
Chavchich
Australian Army Malaria Institute, Enoggera, Brisbane, QLD, Australia.
Karin
K
Van Breda
Australian Army Malaria Institute, Enoggera, Brisbane, QLD, Australia.
Kerryn
K
Rowcliffe
Novartis Institute of Tropical Diseases, Singapore.
Thierry T
TT
Diagana
Australian Army Malaria Institute, Enoggera, Brisbane, QLD, Australia.
Michael D
MD
Edstein
D000962:Antimalarials / Q000494:pharmacology*; D000077549:Artemether; D037621:Artemisinins / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D004983:Ethanolamines / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008018:Life Cycle Stages / Q000187:drug effects*; D000078102:Lumefantrine; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D020112:Rhodamine 123 / Q000737:chemistry; D013141:Spiro Compounds / Q000494:pharmacology*
D000962:Antimalarials; D037621:Artemisinins; D004983:Ethanolamines; D005449:Fluorenes; D007211:Indoles; C552304:NITD 609; D013141:Spiro Compounds; D020112:Rhodamine 123; C039060:artenimol; D000077549:Artemether; D000078102:Lumefantrine