title: Evidence for the contribution of the hemozoin synthesis pathway of the murine Plasmodium yoelii to the resistance to artemisinin-related drugs.
abstract: Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia.
authors.affiliation: CNRS, Laboratoire de Chimie de Coordination, and Université de Toulouse Paul Sabatier, UPS, INPT, LCC, Toulouse, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Witkowski
authors.forename: Joel
authors.initials: J
authors.lastname: Lelièvre
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Nicolau-Travers
authors.forename: Xavier
authors.initials: X
authors.lastname: Iriart
authors.forename: Patrice
authors.initials: P
authors.lastname: Njomnang Soh
authors.forename: Fatima
authors.initials: F
authors.lastname: Bousejra-Elgarah
authors.forename: Bernard
authors.initials: B
authors.lastname: Meunier
authors.forename: Antoine
authors.initials: A
authors.lastname: Berry
authors.forename: Françoise
authors.initials: F
authors.lastname: Benoit-Vical
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000494:pharmacology*; D037621:Artemisinins / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D005260:Female; D006418:Heme / Q000378:metabolism; D006420:Hemeproteins / Q000096:biosynthesis*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010967:Plasmodium yoelii / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C529576:HDP protein, Plasmodium falciparum; D006420:Hemeproteins; D015800:Protozoan Proteins; C020753:hemozoin; D006418:Heme; C031327:artemisinin