title: Potent antihematozoan activity of novel bisthiazolium drug T16: evidence for inhibition of phosphatidylcholine metabolism in erythrocytes infected with Babesia and Plasmodium spp.
abstract: A leading bisthiazolium drug, T16, designed to mimic choline, was shown to exert potent antibabesial activity, with 50% inhibitory concentrations of 28 and 7 nM against Babesia divergens and B. canis, respectively. T16 accumulated inside Babesia-infected erythrocytes (cellular accumulation ratio, >60) by a saturable process with an apparent K(m) of 0.65 microM. Subcellular fractionation of Babesia parasites revealed the accumulation of T16 into a low-density fraction, while in malaria-infected erythrocytes a significant fraction of the drug was associated with heme malaria pigment. T16 exerts an early and specific inhibition of the de novo biosynthesis of phosphatidylcholine both in B. divergens- and Plasmodium falciparum-infected erythrocytes. Choline accumulation into isolated Babesia parasites was highly sensitive to inhibition by T16. These data are consistent with the hypothesis that bisthiazolium drugs target the de novo phosphatidylcholine biosynthesis of intraerythrocytic hematozoan parasites. In malaria parasites, which generate ferriprotoporphyrin IX during hemoglobin digestion, T16 binding to heme may enhance the accumulation and activity of the drug. The selectivity of accumulation and potent activity of this class of drug into parasite-infected erythrocytes offers unique advantages over more traditional antihematozoan drugs.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche UMR 5539, CNRS University Montpellier II, F-34095 Montpellier Cedex 5, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Richier
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.forename: Sharon
authors.initials: S
authors.lastname: Wein
authors.forename: Frederic
authors.initials: F
authors.lastname: Boudou
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Bray
authors.forename: Steve A
authors.initials: SA
authors.lastname: Ward
authors.forename: Eric
authors.initials: E
authors.lastname: Precigout
authors.forename: Michèle
authors.initials: M
authors.lastname: Calas
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Dubremetz
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001403:Babesia / Q000187:drug effects* / Q000378:metabolism; D001404:Babesiosis / Q000469:parasitology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology*; D006461:Hemolysis; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D010713:Phosphatidylcholines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C477299:1,2-didecanemethylenebis(4-methyl-5-ethylthiazolium); D000962:Antimalarials; D000981:Antiprotozoal Agents; D010713:Phosphatidylcholines; D013844:Thiazoles