Evidence for the Contribution of the Hemozoin Synthesis Pathway of the Murine Plasmodium yoelii to the Resistance to Artemisinin-Related Drugs

摘要: Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. drug resistance, WHO recommended in 2001 use artemisinin derivatives combination with partner (called ACT) as first-line treatment for uncomplicated malaria, and most malaria-endemic countries have since changed their policies accordingly. Currently, ACT are often last treatments that can effectively rapidly cure infections permitting significantly decrease mortality morbidity due malaria. However, alarming signs emerging resistance along Thai-Cambodian border concern. Through long-term vivo pressures, we been able select murine model resistant artemisinins. We demonstrated artemisinin-based compounds depends on alterations heme metabolism loss hemozoin formation linked down-expression recently identified Heme Detoxification Protein (HDP). These artemisinins strains could be detoxify free by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, confirmed act also like quinolines against via production inhibition. The work proposed here described mechanism action this class molecules model. results should help both reinforce activity avoid emergence spread endoperoxides focusing adequate partners design. Such considerations appear crucial current context early Asia.