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Mode of action of quinoline antimalarial drugs in red blood cells infected by Plasmodium falciparum revealed in vivo

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  • Sergey Kapishnikov
  • Trine Staalsø
  • Yang Yang
  • Jiwoong Lee
  • Ana J Pérez-Berná
  • Eva Pereiro
  • Yang Yang
  • Stephan Werner
  • Peter Guttmann
  • Leslie Leiserowitz
  • Jens Als-Nielsen
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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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number46
Pages (from-to)22946-22952
Number of pages7
ISSN0027-8424
DOIs
Publication statusPublished - 12 Nov 2019

ID: 58999349