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.
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Article Synopsis
- Bis-thiazolium salts are a new class of anti-parasitic drugs targeting phosphatidylcholine biosynthesis in parasites like Plasmodium and Babesia, with albitiazolium currently in clinical trials for severe malaria.
- Albitiazolium shows significant accumulation in infected red blood cells, reaching a 1,000-fold increase, with a critical phase occurring between 90-120 minutes and is not reliant on lysosomes or food vacuole pH, differing from existing treatments like chloroquine.
- The accumulation relies on glucose and is affected by ionophores disrupting ion gradients; this indicates that the drug's mechanism is efficient in targeting infected cells while limiting toxicity, potentially allowing it to evade
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