How malaria parasites become resistant to artemisinin antimalarial drugs

January 02, 2020

Malaria parasite mutations that inhibit the endocytoic appetite for a host's red blood cells may render them resistant to artemisinin, a widely used frontline antimalarial drug, according to a new study, which reveals a key molecular mechanism of drug resistance. The results may help in the development of more effective antimalarial treatments. Malaria, a life-threatening mosquito-borne disease caused by the Plasmodium falciparum parasite, afflicts more than 200 million people worldwide each year. Artemisinin and its derivatives (ART) are among the most effective antimalarial drugs currently used. However, the emergence of Plasmodium parasites resistant to this and other widely used antimalarials puts their effectiveness at risk. Understanding how parasites develop and mediate ART resistance is critically important to combating malaria and preventing the spread of drug resistance. Previous research has linked ART resistance with mutations in the parasite's Kelch13 protein, although the cellular function of Kelch13 and its role in resistance is poorly understood. Jakob Birnbaum and colleagues discovered that Kelch13 and its other associated proteins are essential for young ring-stage parasites to feed upon the host's red blood cells; ART is activated by the parasite's digestion of hemoglobin. However, Birnbaum et al. found that inactivation of all eight Ketch13 proteins decreased hemoglobin uptake, thus reducing ART activation resulting in parasite resistance to the drug. Similarly, reduced levels of Ketch13 proteins and hemoglobin uptake was also observed in wild P. falciparum carrying ART resistance. The results illustrate how mutations that alter Kelch13 protein stability can lead to ART resistance. In a related Perspective, Danushka Marapana and Alan Cowman discuss the study in greater detail.

American Association for the Advancement of Science

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