title: New insight into the mechanism of accumulation and intraerythrocytic compartmentation of albitiazolium, a new type of antimalarial.
abstract: Bis-thiazolium salts constitute a new class of antihematozoan drugs that inhibit parasite phosphatidylcholine biosynthesis. They specifically accumulate in Plasmodium- and Babesia-infected red blood cells (IRBC). Here, we provide new insight into the choline analogue albitiazolium, which is currently being clinically tested against severe malaria. Concentration-dependent accumulation in P. falciparum-infected erythrocytes reached steady state after 90 to 120 min and was massive throughout the blood cycle, with cellular accumulation ratios of up to 1,000. This could not occur through a lysosomotropic effect, and the extent did not depend on the food vacuole pH, which was the case for the weak base chloroquine. Analysis of albitiazolium accumulation in P. falciparum IRBC revealed a high-affinity component that was restricted to mature stages and suppressed by pepstatin A treatment, and thus likely related to drug accumulation in the parasite food vacuole. Albitiazolium also accumulated in a second high-capacity component present throughout the blood cycle that was likely not related to the food vacuole and also observed with Babesia divergens-infected erythrocytes. Accumulation was strictly glucose dependent, drastically inhibited by H+/K+ and Na+ ionophores upon collapse of ionic gradients, and appeared to be energized by the proton-motive force across the erythrocyte plasma membrane, indicating the importance of transport steps for this permanently charged new type of antimalarial agent. This specific, massive, and irreversible accumulation allows albitiazolium to restrict its toxicity to hematozoa-infected erythrocytes. The intraparasitic compartmentation of albitiazolium corroborates a dual mechanism of action, which could make this new type of antimalarial agent resistant to parasite resistance.
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier 2, Montpellier, France vial@univ-montp2.fr wein@univ-montp2.fr.
authors.forename: Sharon
authors.initials: S
authors.lastname: Wein
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier 2, Montpellier, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Tran Van Ba
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier 2, Montpellier, France.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Maynadier
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier 2, Montpellier, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Bordat
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier 2, Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Perez
authors.affiliation: Institut des Biomolécules Max Mousseron, CNRS UMR 5247, Université Montpellier 2, Montpellier, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Peyrottes
authors.affiliation: Sanofi, TSU Infectious Diseases Unit, Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Fraisse
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier 2, Montpellier, France vial@univ-montp2.fr wein@univ-montp2.fr.
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
mesh_terms: D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D001403:Babesia / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D010963:Plasmodium falciparum / Q000187:drug effects; D018892:Proton-Motive Force / Q000187:drug effects; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C499114:1,12-bis(4-methyl-5-(2-hydroxyethyl)thiazol-3-ium-3-yl)dodecane; D000962:Antimalarials; D013844:Thiazoles