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Chapter 22 : Artemisinin-Resistant Malaria

Authors: Rick M. Fairhurst1, Arjen M. Dondorp2
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Affiliations: 1: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852; 2: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand; 3: Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom
Content Type: Monograph
Publication Year: 2016

Category: Bacterial Pathogenesis; Clinical Microbiology

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Abstract:

According to the World Health Organization (WHO), 3.2 billion people remain at risk of malaria, and an estimated 214 million new cases of malaria and 438,000 deaths occurred in 2015 ( ). Reducing this disease burden continues to rely heavily on the availability and proper use of effective antimalarial drugs. Artemisinin and its derivatives (artesunate, artemether, and dihydroartemisinin [DHA]), referred to collectively as artemisinins, are sesquiterpene lactones with potent activity against nearly all blood stages of parasites. These include asexual stages (rings, trophozoites, and schizonts), which cause the clinical manifestations of malaria, and sexual stages (immature gametocytes), which give rise to the mature gametocytes that transmit infection through mosquitoes to other humans. These blood stages, but not others (merozoites, which invade red blood cells [RBCs], and mature gametocytes), are susceptible to artemisinins because they actively digest hemoglobin as they develop within RBCs. It is believed that the heme-associated iron released from this process cleaves the endoperoxide moiety of artemisinins, thereby forming the reactive oxygen species that target nucleophilic groups in parasite proteins and lipids. In an unbiased chemical proteomics analysis ( ), Wang et al. found that artemisinin covalently binds 124 parasite proteins, many of which are involved in biological processes that are essential for parasite survival, and they suggested that this constellation of chemical reactions kills parasites.

Citation: Fairhurst R, Dondorp A. 2016. Artemisinin-Resistant Malaria, p 409-429. In Scheld W, Hughes J, Whitley R (ed), Emerging infections 10. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EI10-0013-2016
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Artemisinin-Resistant Plasmodium falciparum Malaria
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Citation: Fairhurst R, Dondorp A. 2016. Artemisinin-Resistant Malaria, p 409-429. In Scheld W, Hughes J, Whitley R (ed), Emerging infections 10. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EI10-0013-2016
/content/10.1128/9781555819453.chap22.fig22-1
Figure 1

Dynamics of parasite clearance by artemisinins and other antimalarial drugs. In sensitive infections, fast-acting and rapidly cleared artemisinins reduce the parasite load by a factor of 10,000 per 48-h asexual-stage parasite cycle. In partially resistant infections, artemisinins reduce the parasite load by only by a factor of 100 per cycle, a parasite clearance rate similar to that of slower-acting drugs, such as quinine. Another unique and beneficial feature of artemisinins is their broad stage specificity, but this seems to be compromised in resistant parasites in SEA. Parasites that are at the early ring stage during the brief exposure to rapidly eliminated artemisinins have reduced susceptibility, resulting in delayed parasite clearance following treatment with an artesunate monotherapy or ACT. Reproduced from reference with permission.

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10.1128/9781555819453/fig22-1.gif
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Figure 1

Dynamics of parasite clearance by artemisinins and other antimalarial drugs. In sensitive infections, fast-acting and rapidly cleared artemisinins reduce the parasite load by a factor of 10,000 per 48-h asexual-stage parasite cycle. In partially resistant infections, artemisinins reduce the parasite load by only by a factor of 100 per cycle, a parasite clearance rate similar to that of slower-acting drugs, such as quinine. Another unique and beneficial feature of artemisinins is their broad stage specificity, but this seems to be compromised in resistant parasites in SEA. Parasites that are at the early ring stage during the brief exposure to rapidly eliminated artemisinins have reduced susceptibility, resulting in delayed parasite clearance following treatment with an artesunate monotherapy or ACT. Reproduced from reference with permission.

Citation: Fairhurst R, Dondorp A. 2016. Artemisinin-Resistant Malaria, p 409-429. In Scheld W, Hughes J, Whitley R (ed), Emerging infections 10. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EI10-0013-2016
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Figure 2

kelch13 (K13) protein. The parasite K13 protein consists of -specific sequences, a BTB-POZ domain, and six kelch domains that are predicted to form a six-blade propeller. In the structural model, the original M476I mutation discovered by Ariey et al. ( ) and six other mutations associated with artemisinin resistance in SEA are shown. Reproduced from reference with permission.

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10.1128/9781555819453/fig22-2.gif
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Figure 2

kelch13 (K13) protein. The parasite K13 protein consists of -specific sequences, a BTB-POZ domain, and six kelch domains that are predicted to form a six-blade propeller. In the structural model, the original M476I mutation discovered by Ariey et al. ( ) and six other mutations associated with artemisinin resistance in SEA are shown. Reproduced from reference with permission.

Citation: Fairhurst R, Dondorp A. 2016. Artemisinin-Resistant Malaria, p 409-429. In Scheld W, Hughes J, Whitley R (ed), Emerging infections 10. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EI10-0013-2016
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Figure 3

Recently proposed mechanisms of artemisinin sensitivity and resistance in . In artemisinin-sensitive parasites, wild-type K13 (green) binds a putative transcription factor and targets it for degradation. In artemisinin-resistant parasites, mutant K13 (red) fails to bind this transcription factor, which translocates to the nucleus and upregulates genes involved in the antioxidant response. In this “pre-prepared” state, parasites are better able to handle the oxidative stress that is exerted by activated artemisinins, for example, by repairing and replenishing oxidant-damaged proteins. In artemisinin-sensitive parasites, wild-type K13 (green) binds PI3K and targets it for degradation. In artemisinin-resistant parasites, mutant K13 (red) fails to bind PI3K, leading to increased PI3K activity and PI3P levels. In this “prepared” state, high PI3P levels are presumably able to promote the survival of parasites exposed to artemisinins, for example, by mediating membrane fusion events involved in parasite growth. Reproduced from reference with permission.

10.1128/9781555819453/fig22-3_thmb.gif
10.1128/9781555819453/fig22-3.gif
Image of Figure 3
Figure 3

Recently proposed mechanisms of artemisinin sensitivity and resistance in . In artemisinin-sensitive parasites, wild-type K13 (green) binds a putative transcription factor and targets it for degradation. In artemisinin-resistant parasites, mutant K13 (red) fails to bind this transcription factor, which translocates to the nucleus and upregulates genes involved in the antioxidant response. In this “pre-prepared” state, parasites are better able to handle the oxidative stress that is exerted by activated artemisinins, for example, by repairing and replenishing oxidant-damaged proteins. In artemisinin-sensitive parasites, wild-type K13 (green) binds PI3K and targets it for degradation. In artemisinin-resistant parasites, mutant K13 (red) fails to bind PI3K, leading to increased PI3K activity and PI3P levels. In this “prepared” state, high PI3P levels are presumably able to promote the survival of parasites exposed to artemisinins, for example, by mediating membrane fusion events involved in parasite growth. Reproduced from reference with permission.

Citation: Fairhurst R, Dondorp A. 2016. Artemisinin-Resistant Malaria, p 409-429. In Scheld W, Hughes J, Whitley R (ed), Emerging infections 10. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EI10-0013-2016
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Tables

Artemisinin-Resistant Plasmodium falciparum Malaria
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Citation: Fairhurst R, Dondorp A. 2016. Artemisinin-Resistant Malaria, p 409-429. In Scheld W, Hughes J, Whitley R (ed), Emerging infections 10. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EI10-0013-2016
/content/10.1128/9781555819453.chap22.tab22-1
TABLE 1

K13-propeller mutations, according to propeller blade, geographic location, and association with artemisinin resistance

Generic image for table
TABLE 1

K13-propeller mutations, according to propeller blade, geographic location, and association with artemisinin resistance

Citation: Fairhurst R, Dondorp A. 2016. Artemisinin-Resistant Malaria, p 409-429. In Scheld W, Hughes J, Whitley R (ed), Emerging infections 10. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EI10-0013-2016
/content/10.1128/9781555819453.chap22.tab22-2
TABLE 2

Current status of artemisinin resistance and ACT options for treating uncomplicated malaria in the GMS

Generic image for table
TABLE 2

Current status of artemisinin resistance and ACT options for treating uncomplicated malaria in the GMS

Citation: Fairhurst R, Dondorp A. 2016. Artemisinin-Resistant Malaria, p 409-429. In Scheld W, Hughes J, Whitley R (ed), Emerging infections 10. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.EI10-0013-2016

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