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Antimicrobial Agents and Chemotherapy, October 2006, p. 3381-3388, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00443-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Potent Antihematozoan Activity of Novel Bisthiazolium Drug T16: Evidence for Inhibition of Phosphatidylcholine Metabolism in Erythrocytes Infected with Babesia and Plasmodium spp.{dagger}

Eric Richier,1,{ddagger} Giancarlo A. Biagini,2,{ddagger} Sharon Wein,1 Frederic Boudou,1 Patrick G. Bray,2 Steve A. Ward,2 Eric Precigout,4 Michèle Calas,3 Jean-François Dubremetz,1 and Henri J. Vial1*

Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5539,1 CNRS UMR 5810, Université Montpellier II Place E. Bataillon, 34095 Montpellier Cedex 05, France,3 Molecular and Biochemical Parasitology Group, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, United Kingdom,2 ERT 1038 "Vaccination antiparasitaire", UFR Pharmacie, 15 avenue Charles Flahault, F-34093 Montpellier Cedex 05, France4

Received 8 April 2006/ Returned for modification 15 May 2006/ Accepted 11 July 2006

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 Km of 0.65 µM. 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.

* Corresponding author. Mailing address: UMR 5539 CNRS University Montpellier II, F-34095 Montpellier Cedex 5, France. Phone: 33-4-6714-3745. Fax: 33-4-6714-4286. E-mail: vial{at}univ-montp2.fr.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

{ddagger} These authors contributed equally to this study.

Antimicrobial Agents and Chemotherapy, October 2006, p. 3381-3388, Vol. 50, No. 10
0066-4804/06/$08.00+0     doi:10.1128/AAC.00443-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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