Drug resistance in Plasmodium

Key Points

  • Resistance to frontline artemisinins and partner drugs is now causing the failure of artemisinin-based combination therapies against Plasmodium falciparum in southeast Asia.

  • Triple artemisinin-based combination therapies are being developed, but their design and deployment require an understanding of background resistance and associated genetic mutations of the parasite populations being targeted.

  • P. falciparum Kelch 13 (PfKelch13), the marker for artemisinin resistance in P. falciparum malaria, is not an enzyme or a pump but rather is predicted to be a substrate adapter for a cullin E3 ligase, with a putative substrate of P. falciparum phosphatidylinositol 3-kinase (PfPI3K) and a redox sensor.

  • Mutation in pfkelch13 appears to increase parasite phosphatidylinositol-3-phosphate (PtdIns3P) as well as the unfolded protein response, and both have been proposed as mechanisms of artemisinin resistance.

  • Additional PfKelch13-independent mechanisms of artemisinin resistance have appeared in southeast Asia.

  • The identification of mechanisms of resistance to artemisinin and its partner drugs as well as of new targets for chemotherapy that can eliminate resistant infection in both symptomatic and asymptomatic populations is needed for malaria elimination.

Abstract

A marked decrease in malaria-related deaths worldwide has been attributed to the administration of effective antimalarials against Plasmodium falciparum, in particular, artemisinin-based combination therapies (ACTs). Increasingly, ACTs are also used to treat Plasmodium vivax, the second major human malaria parasite. However, resistance to frontline artemisinins and partner drugs is now causing the failure of P. falciparum ACTs in southeast Asia. In this Review, we discuss our current knowledge of markers and mechanisms of resistance to artemisinins and ACTs. In particular, we describe the identification of mutations in the propeller domains of Kelch 13 as the primary marker for artemisinin resistance in P. falciparum and explore two major mechanisms of resistance that have been independently proposed: the activation of the unfolded protein response and proteostatic dysregulation of parasite phosphatidylinositol 3- kinase. We emphasize the continuing challenges and the imminent need to understand mechanisms of resistance to improve parasite detection strategies, develop new combinations to eliminate resistant parasites and prevent their global spread.

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Figure 1: Life cycle of Plasmodium falciparum and epidemiology of antimalarial drug resistance.
Figure 2: Schematic and structural representation of Plasmodium falciparum Kelch 13 and its hypothesized function as a substrate adapter for a cullin E3 ligase.
Figure 3: Model of protein quality control in the endoplasmic reticulum lumen and cytoplasm of eukaryotes illustrating mechanisms of artemisinin resistance in Plasmodium falciparum.
Figure 4: A working model for heterogeneity in levels of artemisinin resistance.

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Acknowledgements

The authors apologize to colleagues whose work could not be cited owing to the broad scope of the Review and space limitation. They thank members of the Haldar laboratory for insightful discussion. Work in the authors' laboratories was supported by the US National Institutes of Health (R01 HL069630 and HL130330) and India Government Department of Science and Technology (ECR/2015/000387) and Department of Biotechnology Ramalingaswami Re-entry Fellowship (BT/HRD/35/02/2006).

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K.H., S.B. and I.S. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Kasturi Haldar.

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The authors declare no competing financial interests.

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Country/area and Antimalarial Drug Therapy used (WHO, 2016) (DOC 47 kb)

Glossary

Sporozoites

A malaria parasite stage that is injected by the mosquito and that infects liver cells.

Merozoites

A malaria parasite stage that infects red blood cells (also known as erythrocytes).

Endoperoxide

A peroxide group (O–O) that bridges two atoms of a larger molecule and whose cleavage gives rise to reactive free radicals that can oxidize and aggregate proteins (as well as DNA and lipids).

Proteopathy

A disease state where proteins become structurally abnormal and disrupt cellular function.

Proteostasis

A network process or system that integrates translation, signalling pathways, molecular chaperones and protein degradation to enable cells to control the abundance and folding of the proteome.

Parasitaemia

The number of infected red cells per total number of red cells.

Autophagosome

A double-membraned vesicle containing cellular material slated to be degraded by autophagy.

Macroautophagy

A process by which a membrane or phagophore forms near cargo and then expands until it encloses the cargo, which is subsequently degraded by autophagy. Macroautophagy depends on phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and its lipid product phosphatidylinositol-3-phosphate (PtdIns3P).

Apicoplast

An organelle that is a remnant of a non-photosynthetic plastid found in many apicomplexan parasites, including Plasmodium falciparum.

Haemoglobinopathies

Single-gene disorders that result in abnormal structure of the haemoglobin molecule.

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Haldar, K., Bhattacharjee, S. & Safeukui, I. Drug resistance in Plasmodium. Nat Rev Microbiol 16, 156–170 (2018). https://doi.org/10.1038/nrmicro.2017.161

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