Potent antihematozoan activity of novel bisthiazolium drug T16: Evidence for inhibition of phosphatidylcholine metabolism in erythrocytes infected with Babesia and Plasmodium spp.

Richier, E., Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Wein, S., Boudou, F., Bray, Patrick, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192, Precigout, E., Calas, M., Dubremetz, J. F. and Vial, H. J. (2006) 'Potent antihematozoan activity of novel bisthiazolium drug T16: Evidence for inhibition of phosphatidylcholine metabolism in erythrocytes infected with Babesia and Plasmodium spp.'. Antimicrobial Agents and Chemotherapy, Vol 50, Issue 10, pp. 3381-3388.

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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 mu M. 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 falcipartun-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 intracrythrocytic 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.

Item Type:	Article
Subjects:	QV Pharmacology > QV 34 Experimental pharmacology (General) QV Pharmacology > QV 38 Drug action. QX Parasitology > Protozoa > QX 123 Apicomplexa QX Parasitology > Protozoa > QX 135 Plasmodia
Faculty: Department:	Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI):	https://doi.org/10.1128/AAC.00443-06
Depositing User:	Martin Chapman
Date Deposited:	14 Feb 2011 14:46
Last Modified:	17 Jul 2020 10:57
URI:	https://archive.lstmed.ac.uk/id/eprint/1582

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