S. Kapishnikov, T. Staalsø, Yang Yang
Oct 28, 2019
Citations
2
Influential Citations
53
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Quality indicators
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abstract
Significance The most widely used antimalarial drugs belong to the quinoline family. The question of their mode of action has been open for centuries. It has been recently narrowed down to whether these drugs interfere with the process of crystallization of heme in the malaria parasite. To date, all studies of the drug action on heme crystals have been done either on model systems or on dried parasites, which yielded limited data and ambiguity. This study was done in actual parasites in their near-native environment, revealing the mode of action of these drugs in vivo. The approach adopted in this study can be extended to other families of antimalarial drugs, such as artemisinins, provided appropriate derivatives can be synthesized. The most widely used antimalarial drugs belong to the quinoline family. Their mode of action has not been characterized at the molecular level in vivo. We report the in vivo mode of action of a bromo analog of the drug chloroquine in rapidly frozen Plasmodium falciparum-infected red blood cells. The Plasmodium parasite digests hemoglobin, liberating the heme as a byproduct, toxic to the parasite. It is detoxified by crystallization into inert hemozoin within the parasitic digestive vacuole. By mapping such infected red blood cells with nondestructive X-ray microscopy, we observe that bromoquine caps hemozoin crystals. The measured crystal surface coverage is sufficient to inhibit further hemozoin crystal growth, thereby sabotaging heme detoxification. Moreover, we find that bromoquine accumulates in the digestive vacuole, reaching submillimolar concentration, 1,000-fold more than that of the drug in the culture medium. Such a dramatic increase in bromoquine concentration enhances the drug’s efficiency in depriving heme from docking onto the hemozoin crystal surface. Based on direct observation of bromoquine distribution in the digestive vacuole and at its membrane surface, we deduce that the excess bromoquine forms a complex with the remaining heme deprived from crystallization. This complex is driven toward the digestive vacuole membrane, increasing the chances of membrane puncture and spillage of heme into the interior of the parasite.