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Susceptibility

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

Katharina Ehrhardt, Christiane Deregnaucourt, Alice-Anne Goetz, Tzvetomira Tzanova, Valentina Gallo, Paolo Arese, Bruno Pradines, Sophie H. Adjalley, Denyse Bagrel, Stephanie Blandin, Michael Lanzer, Elisabeth Davioud-Charvet
Katharina Ehrhardt
aUMR 7509 CNRS and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), Strasbourg, France
bCenter of Infectious Diseases, Parasitology, Heidelberg University, Heidelberg, Germany
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Christiane Deregnaucourt
cMuseum National d'Histoire Naturelle, UMR 7245 CNRS, Paris Cedex 05, France
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Alice-Anne Goetz
dINSERM, U963, Strasbourg, France
eCNRS, UPR9022, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
fUniversité de Strasbourg, Strasbourg, France
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Tzvetomira Tzanova
gSRSMC Laboratory, UMR CNRS 7565, University of Lorraine, Metz, France
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Valentina Gallo
hDepartment of Oncology, University of Torino Medical School, Turin, Italy
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Paolo Arese
hDepartment of Oncology, University of Torino Medical School, Turin, Italy
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Bruno Pradines
iInstitut de Recherche Biomédicale des Armées, Département des Maladies Infectieuses, Unité de Parasitologie et d'Entomologie, Brétigny sur Orge, France
jAix Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, UM 63, CNRS 7278, IRD 198, INSERM 1095, Marseille, France
kCentre National de Référence du Paludisme, Marseille, France
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Sophie H. Adjalley
lGenome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
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Denyse Bagrel
gSRSMC Laboratory, UMR CNRS 7565, University of Lorraine, Metz, France
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Stephanie Blandin
dINSERM, U963, Strasbourg, France
eCNRS, UPR9022, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France
fUniversité de Strasbourg, Strasbourg, France
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Michael Lanzer
bCenter of Infectious Diseases, Parasitology, Heidelberg University, Heidelberg, Germany
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Elisabeth Davioud-Charvet
aUMR 7509 CNRS and University of Strasbourg, European School of Chemistry, Polymers and Materials (ECPM), Strasbourg, France
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  • ORCID record for Elisabeth Davioud-Charvet
DOI: 10.1128/AAC.02975-15
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ABSTRACT

Previously, we presented the chemical design of a promising series of antimalarial agents, 3-[substituted-benzyl]-menadiones, with potent in vitro and in vivo activities. Ongoing studies on the mode of action of antimalarial 3-[substituted-benzyl]-menadiones revealed that these agents disturb the redox balance of the parasitized erythrocyte by acting as redox cyclers—a strategy that is broadly recognized for the development of new antimalarial agents. Here we report a detailed parasitological characterization of the in vitro activity profile of the lead compound 3-[4-(trifluoromethyl)benzyl]-menadione 1c (henceforth called plasmodione) against intraerythrocytic stages of the human malaria parasite Plasmodium falciparum. We show that plasmodione acts rapidly against asexual blood stages, thereby disrupting the clinically relevant intraerythrocytic life cycle of the parasite, and furthermore has potent activity against early gametocytes. The lead's antiplasmodial activity was unaffected by the most common mechanisms of resistance to clinically used antimalarials. Moreover, plasmodione has a low potential to induce drug resistance and a high killing speed, as observed by culturing parasites under continuous drug pressure. Drug interactions with licensed antimalarial drugs were also established using the fixed-ratio isobologram method. Initial toxicological profiling suggests that plasmodione is a safe agent for possible human use. Our studies identify plasmodione as a promising antimalarial lead compound and strongly support the future development of redox-active benzylmenadiones as antimalarial agents.

FOOTNOTES

    • Received 13 December 2015.
    • Returned for modification 24 February 2016.
    • Accepted 27 May 2016.
    • Accepted manuscript posted online 13 June 2016.
  • Supplemental material for this article may be found at http://dx.doi.org/10.1128/AAC.02975-15.

  • Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites
Katharina Ehrhardt, Christiane Deregnaucourt, Alice-Anne Goetz, Tzvetomira Tzanova, Valentina Gallo, Paolo Arese, Bruno Pradines, Sophie H. Adjalley, Denyse Bagrel, Stephanie Blandin, Michael Lanzer, Elisabeth Davioud-Charvet
Antimicrobial Agents and Chemotherapy Aug 2016, 60 (9) 5146-5158; DOI: 10.1128/AAC.02975-15

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The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites
Katharina Ehrhardt, Christiane Deregnaucourt, Alice-Anne Goetz, Tzvetomira Tzanova, Valentina Gallo, Paolo Arese, Bruno Pradines, Sophie H. Adjalley, Denyse Bagrel, Stephanie Blandin, Michael Lanzer, Elisabeth Davioud-Charvet
Antimicrobial Agents and Chemotherapy Aug 2016, 60 (9) 5146-5158; DOI: 10.1128/AAC.02975-15
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