In vitro activity of mitochondrial ATP synthetase inhibitors against Plasmodium falciparum.
The mitochondrion appears to be essential for the growth of asexual, intraerythrocytic stages of Plasmodium falciparum and may thus be a suitable chemotherapeutic target. The in vitro activity of almitrine, a mitochondrial ATP synthetase inhibitor used for the treatment of hypoxemia, was compared with other mitochondrial inhibitors against chloroquine-susceptible and chloroquine-resistant P. falciparum using an isotopic semimicro drug susceptibility assay. The 50% inhibitory concentration (IC50) values of almitrine (range: 2.6-19.8 microM) were within similar range of values of other mitochondrial ATP synthetase inhibitors and doxycycline, a mitochondrial protein synthesis inhibitor. Almitrine was equally active against chloroquine-susceptible and chloroquine-resistant parasites. Drug combination studies showed no interaction between chloroquine and almitrine. Our results suggest that almitrine, a clinically safe drug, may represent a lead compound with a specific target against the mitochondrial ATP synthetase which may be useful for antimalarial chemotherapy.
Basco
L K
LK
Centre National de Référence pour la Chimiosensibilité du Paludisme, Hôpital Bichat-Claude Bernard, Paris, France.
Le Bras
J
J
D015765:Almitrine / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology*; D001278:Atractyloside / Q000494:pharmacology; D001391:Azo Compounds / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004024:Dicyclohexylcarbodiimide / Q000494:pharmacology; D004351:Drug Resistance; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology; D008928:Mitochondria / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D011794:Quercetin / Q000494:pharmacology; D012235:Rhodamines / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000962:Antimalarials; D001391:Azo Compounds; D012235:Rhodamines; D014475:Uncoupling Agents; D001278:Atractyloside; D004024:Dicyclohexylcarbodiimide; D002738:Chloroquine; D015765:Almitrine; D011794:Quercetin; C047446:janus green; D006180:Proton-Translocating ATPases; D003891:Desipramine