Plasmodium falciparum resistance to artemisinin-based combination therapies

Abstract

Multidrug-resistant Plasmodium falciparum parasites are a major threat to public health in intertropical regions. Understanding the mechanistic basis, origins, and spread of resistance can inform strategies to mitigate its impact and reduce the global burden of malaria. The recent emergence in Africa of partial resistance to artemisinins, the core component of first-line combination therapies, is particularly concerning. Here, we review recent advances in elucidating the mechanistic basis of artemisinin resistance, driven primarily by point mutations in P. falciparum Kelch13, a key regulator of hemoglobin endocytosis and parasite response to artemisinin-induced stress. We also review resistance to partner drugs, including piperaquine and mefloquine, highlighting a key role for plasmepsins 2/3 and the drug and solute transporters P. falciparum chloroquine-resistance transporter and P. falciparum multidrug-resistance protein-1.

Figure 1

Model of select antimalarial drug modes of action and resistance determinants. (a) K13 is involved in endocytosis of hemoglobin-containing host cytosol and trafficking to the DV, where hemoglobin is degraded by parasite proteases, including plasmepsins 2/3 to release peptides and heme. Fe²⁺ heme activates ART derivatives via cleavage of their endoperoxide bridge. The 4-aminoquinolines (CQ, PPQ, ADQ, and PND) act primarily by inhibiting biomineralization of toxic heme to inert hemozoin. LMF, MFQ, and ART derivatives partially inhibit hemozoin formation and are thought to act on primary targets in the cytosol. PfMDR1 (WT) transports diverse compounds from the cytosol into the DV. PfCRT (WT) does not mediate drug transport, but transports globin-derived peptide residues from the DV to the parasite cytosol. (b) Mutations in PfMDR1 and PfCRT (MUT) are thought to decrease and confer drug-transport capacity, respectively, reducing drug accumulation in the DV and increasing concentration in the cytosol, resulting in 4-aminoquinoline resistance and increased susceptibility to LMF, MFQ, and ART. Hb, hemoglobin; RBC, red blood cell.