The Threat of Artemisinin-Resistant Malaria

Dondorp, Arjen M.; Fairhurst, Rick M.; Slutsker, Laurence; MacArthur, John; Breman, Joel G.; Guérin, Philippe J.; Wellems, Thomas E.; Ringwald, Pascal; Newman, Robert D.; Plowe, Christopher V.

doi:10.1056/nejmp1108322

Cited by 245 publications

(211 citation statements)

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“…With the recent reports of resistance potentially emerging to artemisinin (16), the development of novel compounds that can fulfill a function similar to that of artemisinin to block both infection and transmission will help alleviate the burden on current first-line antimalarial therapies. The compounds described here represent a class of chemicals that will need to be further developed and optimized to design the next generation of specific, selective, and safe dual-function antimalarials that can block both infection and transmission.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission

Bobenchik

Witola

Augagneur

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Efficient transmission of Plasmodium species between humans and Anopheles mosquitoes is a major contributor to the global burden of malaria. Gametocytogenesis, the process by which parasites switch from asexual replication within human erythrocytes to produce male and female gametocytes, is a critical step in malaria transmission and Plasmodium genetic diversity. Nothing is known about the pathways that regulate gametocytogenesis and only few of the current drugs that inhibit asexual replication are also capable of inhibiting gametocyte development and blocking malaria transmission. Here we provide genetic and pharmacological evidence indicating that the pathway for synthesis of phosphatidylcholine in Plasmodium falciparum membranes from host serine is essential for parasite gametocytogenesis and malaria transmission. Parasites lacking the phosphoethanolamine N-methyltransferase enzyme, which catalyzes the limiting step in this pathway, are severely altered in gametocyte development, are incapable of producing mature-stage gametocytes, and are not transmitted to mosquitoes. Chemical screening identified 11 inhibitors of phosphoethanolamine N-methyltransferase that block parasite intraerythrocytic asexual replication and gametocyte differentiation in the low micromolar range. Kinetic studies in vitro as well as functional complementation assays and lipid metabolic analyses in vivo on the most promising inhibitor NSC-158011 further demonstrated the specificity of inhibition. These studies set the stage for further optimization of NSC-158011 for development of a class of dual activity antimalarials to block both intraerythrocytic asexual replication and gametocytogenesis.H uman malaria parasites exhibit a complex life cycle consisting of asexual phases within human hepatocytes and erythrocytes, with the latter directly responsible for disease manifestations. Within red blood cells, these parasites can also undergo gametocytogenesis, a process during which they interrupt their asexual replication and differentiate to form morphologically and functionally distinct sexual-stage gametocytes (1). These sexual forms serve as precursors for male and female gametes, which develop in the mosquito where they undergo mating, meiosis and several mitotic cycles to produce sporozoites. In Plasmodium falciparum, the causative agent of the most severe form of human malaria, the progression from immature stage I to mature stage V gametocytes takes ∼10 d (2). However, the biological processes that regulate gametocytogenesis remain unknown. Thorough understanding of these processes is crucial to the development of a new generation of dual activity antimalarials that can inhibit both infection and transmission.Phosphatidylcholine (PC), the predominant phospholipid produced by malaria parasites, plays essential structural and regulatory roles in parasite development and differentiation (reviewed in ref.3). Lipid metabolic and genetic studies in P. falciparum have demonstrated the presence of two pathways for PC biosynthesis (Fig. S1): ...

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Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission

Bobenchik

Witola

Augagneur

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…12 However, such strong pressure on vector and parasite populations will inevitably lead to the selection and spread of resistant strains of mosquitoes and malaria parasites, respectively. Resistance to artemisinins, which has emerged in malaria parasites in southeast Asia, 13 will probably spread globally. Resistance to all four classes of insecticide available for indoor residual spraying (including the pyrethroids, the only insecticides currently available for impregnation of bednets), has now been documented in sub-Saharan African.…”

Section: Introductionmentioning

confidence: 99%

Socioeconomic development as an intervention against malaria: a systematic review and meta-analysis

et al. 2013

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Official URL: http://dx.doi.org/10.1016/S0140-6736(13)60851-X More details/abstract: Background: Future progress in tacking malaria mortality will probably be hampered by the development of resistance to drugs and insecticides and by the contraction of aid budgets. Historically, control was often achieved without malaria specific interventions. Our aim was to assess whether socioeconomic development can contribute to malaria control. Methods: We did a systematic review and meta-analysis to assess whether the risk of malaria in children aged 0-15 years is associated with socioeconomic status. We searched Medline, Web of Science, Embase, the Cochrane Database of Systematic Reviews, the Campbell Library, the Centre for Reviews and Dissemination, Health Systems Evidence, and the Evidence for Policy and Practice Information and Co-ordinating Centre evidence library for studies published in English between Jan 1, 1980, and July 12, 2011, that measured socioeconomic status and parasitologically confirmed malaria or clinical malaria in children. Unadjusted and adjusted effect estimates were combined in fixed effects and random-effects meta-analyses, with a subgroup analysis for different measures of socioeconomic status. We used funnel plots and Egger's linear regression to test for publication bias. Findings: Of 4696 studies reviewed, 20 met the criteria for inclusion in the qualitative analysis, and 15 of these reported the necessary data for inclusion in the meta-analysis. The odds of malaria infection were higher in the poorest children than in the least poor children (unadjusted odds ratio [OR] 1•66, 95% CI 1•35-2•05, p<0•001, I²=68%; adjusted OR 2•06, 1•42-2•97, p<0•001, I²=63%), an effect that was consistent across subgroups. Interpretation: Although we would not recommend discontinuation of existing malaria control efforts, we believe that increased investment in interventions to support socioeconomic development is warranted, since such interventions could prove highly effective and sustainable against malaria in the long term. Version: Accepted Author ManuscriptTerms of use: This work has been licensed by the copyright holder for distribution in electronic format via any medium for the lifetime of the OpenDocs repository for the purpose of free access without charge. NOTICE: this is the author's version of a work that was accepted for publication in The Lancet. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in The Lancet 382.9896 (2013) SummaryBackground Future progress in tacking malaria mortality will probably be hampered by the development of resistance to drugs and insecticides and by the contraction of aid budgets. Historically, control was often achieved without malariaspecific interventions. Our aim was to assess whether socioeconomic de...

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“…Malaria has been treated with artemisinin derivatives in Asia since the 1970s (2). Extremely fast-acting, artemisinins kill both young ring forms and mature blood-stage parasites (3). The World Health Organization (WHO) recommended in 2001 that artemisinins be used strictly in combination therapies in hopes of delaying the emergence of resistance (2), but ACT treatment failure rates were rising on the Thailand/Cambodia border by 2006 (4,5) and progressively prolonged parasite clearance after treatment with artemisinin derivatives soon followed (6)(7)(8).…”

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confidence: 99%

“…The World Health Organization (WHO) recommended in 2001 that artemisinins be used strictly in combination therapies in hopes of delaying the emergence of resistance (2), but ACT treatment failure rates were rising on the Thailand/Cambodia border by 2006 (4,5) and progressively prolonged parasite clearance after treatment with artemisinin derivatives soon followed (6)(7)(8). This evidence that artemisinin resistance has emerged in western Cambodia, historically an epicenter of drug-resistant malaria, is an ominous development that threatens the recent major global investment in ACTs (3). If genetically heritable artemisinin resistance has emerged, it can be expected to follow historical patterns of antimalarial resistance (9) and disseminate globally, at immense cost to human life.…”

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confidence: 99%

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

Takala-Harrison

Clark

Jacob

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The recent emergence of artemisinin-resistant Plasmodium falciparum malaria in western Cambodia could threaten prospects for malaria elimination. Identification of the genetic basis of resistance would provide tools for molecular surveillance, aiding efforts to contain resistance. Clinical trials of artesunate efficacy were conducted in Bangladesh, in northwestern Thailand near the Myanmar border, and at two sites in western Cambodia. Parasites collected from trial participants were genotyped at 8,079 single nucleotide polymorphisms (SNPs) using a P. falciparum-specific SNP array. Parasite genotypes were examined for signatures of recent positive selection and association with parasite clearance phenotypes to identify regions of the genome associated with artemisinin resistance. Four SNPs on chromosomes 10 (one), 13 (two), and 14 (one) were significantly associated with delayed parasite clearance. The two SNPs on chromosome 13 are in a region of the genome that appears to be under strong recent positive selection in Cambodia. The SNPs on chromosomes 10 and 13 lie in or near genes involved in postreplication repair, a DNA damage-tolerance pathway. Replication and validation studies are needed to refine the location of loci responsible for artemisinin resistance and to understand the mechanism behind it; however, two SNPs on chromosomes 10 and 13 may be useful markers of delayed parasite clearance in surveillance for artemisinin resistance in Southeast Asia.drug resistance | genome-wide association | molecular markers

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The Threat of Artemisinin-Resistant Malaria

Cited by 245 publications

References 4 publications

Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission

Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission

Socioeconomic development as an intervention against malaria: a systematic review and meta-analysis

Genetic loci associated with delayed clearance of Plasmodium falciparum following artemisinin treatment in Southeast Asia

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