DetoxFungiV1, Main, Exploration, bibRecord, 000434

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

Identifieur interne : 000434 ( Main/Exploration ); précédent : 000433; suivant : 000435

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

Auteurs : Sergey Kapishnikov [Israël] ; Trine Staals [Danemark] ; Yang Yang [Danemark] ; Jiwoong Lee [Danemark] ; Ana J. Pérez-Berná [Espagne] ; Eva Pereiro [Espagne] ; Yang Yang [France] ; Stephan Werner [Allemagne] ; Peter Guttmann [Allemagne] ; Leslie Leiserowitz [Israël] ; Jens Als-Nielsen [Danemark]

Source :

Proceedings of the National Academy of Sciences of the United States of America [ 1091-6490 ] ; 2019.

RBID : pubmed:31659055

Descripteurs français

KwdFr :
- Antipaludiques (pharmacologie), Cristallisation (MeSH), Humains (MeSH), Hème (composition chimique), Hème (métabolisme), Hémoprotéines (composition chimique), Hémoprotéines (métabolisme), Paludisme à Plasmodium falciparum (métabolisme), Paludisme à Plasmodium falciparum (parasitologie), Paludisme à Plasmodium falciparum (traitement médicamenteux), Plasmodium falciparum (effets des médicaments et des substances chimiques), Plasmodium falciparum (physiologie), Quinoléines (pharmacologie), Érythrocytes (composition chimique), Érythrocytes (métabolisme), Érythrocytes (parasitologie).
MESH :
- composition chimique : Hème, Hémoprotéines, Érythrocytes.
- effets des médicaments et des substances chimiques : Plasmodium falciparum.
- métabolisme : Hème, Hémoprotéines, Paludisme à Plasmodium falciparum, Érythrocytes.
- parasitologie : Paludisme à Plasmodium falciparum, Érythrocytes.
- pharmacologie : Antipaludiques, Quinoléines.
- physiologie : Plasmodium falciparum.
- traitement médicamenteux : Paludisme à Plasmodium falciparum.
- Cristallisation, Humains.

English descriptors

KwdEn :
- Antimalarials (pharmacology), Crystallization (MeSH), Erythrocytes (chemistry), Erythrocytes (metabolism), Erythrocytes (parasitology), Heme (chemistry), Heme (metabolism), Hemeproteins (chemistry), Hemeproteins (metabolism), Humans (MeSH), Malaria, Falciparum (drug therapy), Malaria, Falciparum (metabolism), Malaria, Falciparum (parasitology), Plasmodium falciparum (drug effects), Plasmodium falciparum (physiology), Quinolines (pharmacology).
MESH :
- chemical , chemistry : Heme, Hemeproteins.
- chemical , metabolism : Heme, Hemeproteins.
- chemical , pharmacology : Antimalarials, Quinolines.
- chemistry : Erythrocytes.
- drug effects : Plasmodium falciparum.
- drug therapy : Malaria, Falciparum.
- metabolism : Erythrocytes, Malaria, Falciparum.
- parasitology : Erythrocytes, Malaria, Falciparum.
- physiology : Plasmodium falciparum.
- Crystallization, Humans.

Abstract

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.

DOI: 10.1073/pnas.1910123116
PubMed: 31659055
PubMed Central: PMC6859308

Affiliations:

Allemagne, Danemark, Espagne, France, Israël
Auvergne-Rhône-Alpes, Berlin, Catalogne, Hovedstaden, Rhône-Alpes
Berlin, Copenhague, Grenoble

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000302
to stream Main, to step Curation: 000302

Le document en format XML

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 revealed in vivo.</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antimalarials (pharmacology)</term>
<term>Crystallization (MeSH)</term>
<term>Erythrocytes (chemistry)</term>
<term>Erythrocytes (metabolism)</term>
<term>Erythrocytes (parasitology)</term>
<term>Heme (chemistry)</term>
<term>Heme (metabolism)</term>
<term>Hemeproteins (chemistry)</term>
<term>Hemeproteins (metabolism)</term>
<term>Humans (MeSH)</term>
<term>Malaria, Falciparum (drug therapy)</term>
<term>Malaria, Falciparum (metabolism)</term>
<term>Malaria, Falciparum (parasitology)</term>
<term>Plasmodium falciparum (drug effects)</term>
<term>Plasmodium falciparum (physiology)</term>
<term>Quinolines (pharmacology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Antipaludiques (pharmacologie)</term>
<term>Cristallisation (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Hème (composition chimique)</term>
<term>Hème (métabolisme)</term>
<term>Hémoprotéines (composition chimique)</term>
<term>Hémoprotéines (métabolisme)</term>
<term>Paludisme à Plasmodium falciparum (métabolisme)</term>
<term>Paludisme à Plasmodium falciparum (parasitologie)</term>
<term>Paludisme à Plasmodium falciparum (traitement médicamenteux)</term>
<term>Plasmodium falciparum (effets des médicaments et des substances chimiques)</term>
<term>Plasmodium falciparum (physiologie)</term>
<term>Quinoléines (pharmacologie)</term>
<term>Érythrocytes (composition chimique)</term>
<term>Érythrocytes (métabolisme)</term>
<term>Érythrocytes (parasitologie)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Heme</term>
<term>Hemeproteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Heme</term>
<term>Hemeproteins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antimalarials</term>
<term>Quinolines</term>
</keywords>
<keywords scheme="MESH" qualifier="chemistry" xml:lang="en"><term>Erythrocytes</term>
</keywords>
<keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Hème</term>
<term>Hémoprotéines</term>
<term>Érythrocytes</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Malaria, Falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Erythrocytes</term>
<term>Malaria, Falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Hème</term>
<term>Hémoprotéines</term>
<term>Paludisme à Plasmodium falciparum</term>
<term>Érythrocytes</term>
</keywords>
<keywords scheme="MESH" qualifier="parasitologie" xml:lang="fr"><term>Paludisme à Plasmodium falciparum</term>
<term>Érythrocytes</term>
</keywords>
<keywords scheme="MESH" qualifier="parasitology" xml:lang="en"><term>Erythrocytes</term>
<term>Malaria, Falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antipaludiques</term>
<term>Quinoléines</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Paludisme à Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Crystallization</term>
<term>Humans</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Cristallisation</term>
<term>Humains</term>
</keywords>
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<front><div type="abstract" xml:lang="en">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 <i>Plasmodium falciparum</i>
-infected red blood cells. The <i>Plasmodium</i>
 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.</div>
</front>
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<DateCompleted><Year>2020</Year>
<Month>04</Month>
<Day>06</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>04</Month>
<Day>08</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1091-6490</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>116</Volume>
<Issue>46</Issue>
<PubDate><Year>2019</Year>
<Month>11</Month>
<Day>12</Day>
</PubDate>
</JournalIssue>
<Title>Proceedings of the National Academy of Sciences of the United States of America</Title>
<ISOAbbreviation>Proc Natl Acad Sci U S A</ISOAbbreviation>
</Journal>
<ArticleTitle>Mode of action of quinoline antimalarial drugs in red blood cells infected by <i>Plasmodium falciparum</i>
 revealed in vivo.</ArticleTitle>
<Pagination><MedlinePgn>22946-22952</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1073/pnas.1910123116</ELocationID>
<Abstract><AbstractText>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 <i>Plasmodium falciparum</i>
-infected red blood cells. The <i>Plasmodium</i>
 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.</AbstractText>
<CopyrightInformation>Copyright © 2019 the Author(s). Published by PNAS.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Kapishnikov</LastName>
<ForeName>Sergey</ForeName>
<Initials>S</Initials>
<Identifier Source="ORCID">0000-0003-2560-054X</Identifier>
<AffiliationInfo><Affiliation>Niels Bohr Institute, University of Copenhagen, 2100 Copenhagen, Denmark; sergey.kapishnikov@weizmann.ac.il.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Staalsø</LastName>
<ForeName>Trine</ForeName>
<Initials>T</Initials>
<AffiliationInfo><Affiliation>Department of Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.</Affiliation>
</AffiliationInfo>
<AffiliationInfo><Affiliation>Department of Clinical Microbiology, Copenhagen University Hospital, 2100 Copenhagen, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yang</LastName>
<ForeName>Yang</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>Department of Chemistry, University of Copenhagen, 2100 Copenhagen, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Lee</LastName>
<ForeName>Jiwoong</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Chemistry, University of Copenhagen, 2100 Copenhagen, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pérez-Berná</LastName>
<ForeName>Ana J</ForeName>
<Initials>AJ</Initials>
<AffiliationInfo><Affiliation>MISTRAL Beamline Experiments Division, ALBA Synchrotron Light Source, 08290 Barcelona, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pereiro</LastName>
<ForeName>Eva</ForeName>
<Initials>E</Initials>
<Identifier Source="ORCID">0000-0001-7626-5935</Identifier>
<AffiliationInfo><Affiliation>MISTRAL Beamline Experiments Division, ALBA Synchrotron Light Source, 08290 Barcelona, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yang</LastName>
<ForeName>Yang</ForeName>
<Initials>Y</Initials>
<AffiliationInfo><Affiliation>European Synchrotron Radiation Facility, 38000 Grenoble, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Werner</LastName>
<ForeName>Stephan</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Joint Research Group X-Ray Microscopy, Helmholtz-Zentrum Berlin, 12489 Berlin, Germany.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Guttmann</LastName>
<ForeName>Peter</ForeName>
<Initials>P</Initials>
<Identifier Source="ORCID">0000-0002-0534-238X</Identifier>
<AffiliationInfo><Affiliation>Joint Research Group X-Ray Microscopy, Helmholtz-Zentrum Berlin, 12489 Berlin, Germany.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Leiserowitz</LastName>
<ForeName>Leslie</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Department of Materials and Interfaces, Weizmann Institute of Science, 76100 Rehovot, Israel.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Als-Nielsen</LastName>
<ForeName>Jens</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Niels Bohr Institute, University of Copenhagen, 2100 Copenhagen, Denmark.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2019</Year>
<Month>10</Month>
<Day>28</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Proc Natl Acad Sci U S A</MedlineTA>
<NlmUniqueID>7505876</NlmUniqueID>
<ISSNLinking>0027-8424</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000962">Antimalarials</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D006420">Hemeproteins</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D011804">Quinolines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>39404-00-7</RegistryNumber>
<NameOfSubstance UI="C020753">hemozoin</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>42VZT0U6YR</RegistryNumber>
<NameOfSubstance UI="D006418">Heme</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000962" MajorTopicYN="N">Antimalarials</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D003460" MajorTopicYN="N">Crystallization</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004912" MajorTopicYN="N">Erythrocytes</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000469" MajorTopicYN="Y">parasitology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006418" MajorTopicYN="N">Heme</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006420" MajorTopicYN="N">Hemeproteins</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D016778" MajorTopicYN="N">Malaria, Falciparum</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000469" MajorTopicYN="Y">parasitology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010963" MajorTopicYN="N">Plasmodium falciparum</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
<QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011804" MajorTopicYN="N">Quinolines</DescriptorName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="Y">cryo X-ray microscopy</Keyword>
<Keyword MajorTopicYN="Y">drug tracking</Keyword>
<Keyword MajorTopicYN="Y">hemozoin</Keyword>
<Keyword MajorTopicYN="Y">inhibition of crystallization</Keyword>
<Keyword MajorTopicYN="Y">malaria</Keyword>
</KeywordList>
<CoiStatement>The authors declare no competing interest.</CoiStatement>
</MedlineCitation>
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<Month>10</Month>
<Day>30</Day>
<Hour>6</Hour>
<Minute>0</Minute>
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<PubMedPubDate PubStatus="medline"><Year>2020</Year>
<Month>4</Month>
<Day>9</Day>
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<region><li>Auvergne-Rhône-Alpes</li>
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	Serveur d'exploration sur la détoxication des champignons
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Serveur d'exploration sur la détoxication des champignons

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

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

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