Elucidating Mechanisms of Drug-Resistant Plasmodium falciparum

Abstract

Intensified treatment and control efforts since the early 2000s have dramatically reduced the burden of Plasmodium falciparum malaria. However, drug resistance threatens to derail this progress. In this review, we present four antimalarial resistance case studies that differ in timeline, technical approaches, mechanisms of action, and categories of resistance: chloroquine, sulfadoxine-pyrimethamine, artemisinin, and piperaquine. Lessons learned from prior losses of treatment efficacy, drug combinations, and control strategies will help advance mechanistic research into how P. falciparum parasites acquire resistance to current first-line artemisinin-based combination therapies. Understanding resistance in the clinic and laboratory is essential to prolong the effectiveness of current antimalarial drugs and to optimize the pipeline of future medicines.

Keywords: Plasmodium; antimalarials; artemisinin; drug resistance; genetics; genomics; malaria; mutations.

Figure 1.. Plasmodium falciparum life cycle, shared between the human host and the Anopheles mosquito vector.

Adapted from (Lee et al., 2014). Sporozoites, gametocytes, and oocyst stages are genetic population bottlenecks. ABS, asexual blood stages; RBCs, red blood cells.

Figure 2.. Schematic of a P. falciparum trophozoite indicating the intracellular targets of major classes of antimalarials and drug resistance determinants.

ART, artemisinin; ATQ, atovaquone; CQ, chloroquine; Cyt b, cytochrome b; DHFR, dihydrofolate reductase; DHPS, dihydropteroate synthase; Hb, hemoglobin; LMF, lumefantrine; MFQ, mefloquine; PfCRT, P. falciparum chloroquine resistance transporter; PfMDR1, P. falciparum multidrug resistance-1; PPQ, piperaquine; RBC, red blood cell; SP, sulfadoxine-pyrimethamine.

Figure 3.. Model for K13-mediated ART resistance.

(A) Schematic proposing differences in the acute stress response of P. falciparum K13 wild-type (WT) or K13 C580Y early ring-stage parasites exposed to DHA. Parasite genetic backgrounds contribute to variations in the levels of K13 isoform-mediated stress response and subsequent survival. (B) Side-view of the β-propeller of K13 (PDB: 4YY8, residues 444-726) showing cysteines and/or resistance-associated mutations. Cysteine sulfurs are indicated with yellow spheres. The putative oxidative sensor cysteines are all located in a vertical plane inside the β-propeller. (C) An alternate hypothesis of ART resistance is that eIF2α phosphorylation-mediated translational repression during the schizont-to-ring transition might be extended in K13 mutant, ART-resistant parasites. This delayed re-entry into active translation and growth could allow these parasites to survive ART pulses. Parasites could re-enter growth in a stochastic manner, with later recovery permitting survival. Schizont and early ring-stage parasites are shown below. (D) Close-up of one β-sheet (residues 577-615) showing spatial separation of C580 and A578, located on a structured β-strand and on an unstructured loop, respectively. C580Y is a mediator of ART resistance, whereas A578S is not (Menard et al., 2016). Images made with CCP4mg.