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Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure

Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated w...

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Autores principales: Ménard, Sandie, Ben Haddou, Tanila, Ramadani, Arba Pramundita, Ariey, Frédéric, Iriart, Xavier, Beghain, Johann, Bouchier, Christiane, Witkowski, Benoit, Berry, Antoine, Mercereau-Puijalon, Odile, Benoit-Vical, Françoise
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Centers for Disease Control and Prevention 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593447/
https://www.ncbi.nlm.nih.gov/pubmed/26401601
http://dx.doi.org/10.3201/eid2110.150682
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author Ménard, Sandie
Ben Haddou, Tanila
Ramadani, Arba Pramundita
Ariey, Frédéric
Iriart, Xavier
Beghain, Johann
Bouchier, Christiane
Witkowski, Benoit
Berry, Antoine
Mercereau-Puijalon, Odile
Benoit-Vical, Françoise
author_facet Ménard, Sandie
Ben Haddou, Tanila
Ramadani, Arba Pramundita
Ariey, Frédéric
Iriart, Xavier
Beghain, Johann
Bouchier, Christiane
Witkowski, Benoit
Berry, Antoine
Mercereau-Puijalon, Odile
Benoit-Vical, Françoise
author_sort Ménard, Sandie
collection PubMed
description Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy.
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spelling pubmed-45934472015-10-05 Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure Ménard, Sandie Ben Haddou, Tanila Ramadani, Arba Pramundita Ariey, Frédéric Iriart, Xavier Beghain, Johann Bouchier, Christiane Witkowski, Benoit Berry, Antoine Mercereau-Puijalon, Odile Benoit-Vical, Françoise Emerg Infect Dis Research Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy. Centers for Disease Control and Prevention 2015-10 /pmc/articles/PMC4593447/ /pubmed/26401601 http://dx.doi.org/10.3201/eid2110.150682 Text en https://creativecommons.org/licenses/by/4.0/This is a publication of the U.S. Government. This publication is in the public domain and is therefore without copyright. All text from this work may be reprinted freely. Use of these materials should be properly cited.
spellingShingle Research
Ménard, Sandie
Ben Haddou, Tanila
Ramadani, Arba Pramundita
Ariey, Frédéric
Iriart, Xavier
Beghain, Johann
Bouchier, Christiane
Witkowski, Benoit
Berry, Antoine
Mercereau-Puijalon, Odile
Benoit-Vical, Françoise
Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure
title Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure
title_full Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure
title_fullStr Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure
title_full_unstemmed Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure
title_short Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure
title_sort induction of multidrug tolerance in plasmodium falciparum by extended artemisinin pressure
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593447/
https://www.ncbi.nlm.nih.gov/pubmed/26401601
http://dx.doi.org/10.3201/eid2110.150682
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