New Insight into the Mechanism of Accumulation and Intraerythrocytic Compartmentation of Albitiazolium, a New Type of Antimalarial
| العنوان: | New Insight into the Mechanism of Accumulation and Intraerythrocytic Compartmentation of Albitiazolium, a New Type of Antimalarial |
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| المؤلفون: | Suzanne Peyrottes, Marjorie Maynadier, Christophe Tran Van Ba, Yann Bordat, Laurent Fraisse, Julie Perez, Sharon Wein, Henri Vial |
| المساهمون: | Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Therapeutic Strategic Unit for Infectious Diseases Unit (TSU), SANOFI Recherche |
| المصدر: | Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2014, 58 (9), pp.5519-27. ⟨10.1128/AAC.00040-14⟩ |
| بيانات النشر: | American Society for Microbiology, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Erythrocytes, Plasmodium falciparum, Drug Resistance, Babesia, Phosphatidylcholine Biosynthesis, Cell membrane, Antimalarials, 03 medical and health sciences, chemistry.chemical_compound, Chloroquine, parasitic diseases, medicine, Food vacuole, Humans, Pharmacology (medical), Antimalarial Agent, Malaria, Falciparum, Mechanisms of Action: Physiological Effects, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 030306 microbiology, Chemiosmosis, Cell Membrane, Proton-Motive Force, biology.organism_classification, 3. Good health, Cell biology, Thiazoles, Infectious Diseases, medicine.anatomical_structure, Biochemistry, chemistry, Pepstatin, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1098-6596 0066-4804 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a768a510b9ad05c42baa729b9f3a564d https://doi.org/10.1128/aac.00040-14 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a768a510b9ad05c42baa729b9f3a564d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10986596 00664804 |
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