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.