Plasmodium falciparum resistance to artemisinin-based combination therapies (ACTs) started to crop up around 2007. Infections, especially in the Greater Mekong area of Southeast Asia, seemingly survived treatment. This was largely due to the pairing of artemisinin derivatives with older drugs that had existing resistance problems. But some experts think the emergence of partial resistance to artemisinin itself—which allows parasites to persist for longer in the body following treatment—could also play a role.
ACT of Resistance
Plasmodium falciparum resistance to artemisinin-based combination therapies (ACTs) started to crop up around 2007. This largely arose from pairing artemisinin derivatives with older drugs that had existing resistance problems. But the emergence of partial resistance to artemisinin itself—which allows parasites to persist for longer in the body following treatment—may also play a role.
Partial artemisinin resistance
Researchers have linked partial resistance to artemisinin-derived drugs with several mutations in the kelch13 gene, which encodes a binding protein whose role in the parasite’s ability to persist is still unclear. Delayed parasite clearance has also been linked to a prolonged ring stage, which appears to be the only part of the parasite’s lifecycle during which it is able to partially survive artemisinin derivatives such as artemether, artesunate, or dihydroartemisinin. A single dose of these ACT ingredients stays in the body for only a few hours, and patients are typically treated with an artemisinin derivative for only the first couple of day of malaria therapy, so it’s thought that the prolonged ring stage may help the parasites survive the therapy. Preliminary evidence suggests that resistant parasites also rush through the subsequent trophozoite stage, which appears to be the most susceptible to artemisinin.
Partner drug resistance
In red blood cells, P. falciparum digests human hemoglobin to feed itself. In addition to amino acids, this releases toxic heme. Normally, the parasite polymerizes the heme into harmless clumps of hemozoin or degrades it through a handful of poorly understood pathways. But most ACT partner drugs inhibit detoxification. Some partner drugs also attack the parasite through other mechanisms. Here are examples of how P. falciparum strains resist these drugs.
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