Fitness of artemisinin-resistant<i>Plasmodium falciparum in vitro</i>

Hott, Amanda; Tucker, Matthew S.; Casandra, Debora; Sparks, Kansas; Kyle, Dennis E.

doi:10.1093/jac/dkv199

Cited by 26 publications

(29 citation statements)

References 35 publications

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“…The artemisinincombination therapy (ACT) is recommended by the WHO as the first-line treatment for P. falciparum infections in all endemic regions [1] and also in nonendemic countries like Qatar [4]. In spite of these efforts, there have been sporadic reports of an invivo and an in-vitro artemisinin resistance during the last few years [43][44][45]. However, the mechanism of artemisinin resistance is still under investigation.…”

Section: Discussionmentioning

confidence: 99%

“…But at the same time, many studies have proved that the quadruple Pfdhfr/Pfdhps combined haplotype (59R + 108N/437G + 540E) are directly associated with either adequate clinical and parasitological response, early treatment failures or late parasitological failures to SP [11,35,57]. Similarly, the reduced efficacy of artemisinin associated with the presence of the functional mutation in the K-13 gene [44,45].…”

Section: Discussionmentioning

confidence: 99%

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Molecular surveillance of putative drug resistance markers of antifolate and artemisinin among importedPlasmodium falciparumin Qatar

Bansal

Bharti

Acharya

et al. 2019

Pathogens and Global Health

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Malaria remains a significant public health challenge and is of global importance. Imported malaria is a growing problem in non-endemic areas throughout the world and also in Qatar due to a massive influx of migrants from endemic countries. Antimalarial drug resistance is an important deterrent in our fight against malaria today. Molecular markers mirror intrinsic antimalarial drug resistance and their changes precede clinical resistance. Thus, in the present study, molecular markers of sulphadoxine-pyrimethamine (Pfdhfr and Pfdhps) and artemisinin (PfATPase6 and Pfk13) were sequenced to determine the drug resistance genotypes among 118 imported P. falciparum isolates in Qatar, between 2013 and 2016. All the isolates had mutant Pfdhfr alleles, with either double mutant (51I/108N) (59.3%) or triple mutant (51I, 59R and 108N) (30.6%) genotypes. I164L substitution was not found in this study. In case of Pfdhps, majority of the samples were carriers of either single (S436A/ A437G/ K540E) mutant (47.2%) or double (S436A/K540E, A437G/K540E, K540E/A581G) mutant (39.8%). A single novel point mutation (431V) was observed in the samples originated from Nigeria and Ghana. Polymorphisms in PfATPase6 were absent and only one non-synonymous mutation in Pfk13 was found at codon G453A from a sample of Kenyan origin. High levels of sulphadoxinepyrimethamine resistance in the present study provide potential information about the spread of antimalarial drug resistance and will be beneficial for the treatment of imported malaria cases in Qatar.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular surveillance of putative drug resistance markers of antifolate and artemisinin among importedPlasmodium falciparumin Qatar

Bansal

Bharti

Acharya

et al. 2019

Pathogens and Global Health

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“…It is possible that such mutations confer a fitness cost to parasites in the absence of artemisinin pressure (35). This supposition is supported by the fact that in parasite populations not exposed to artemisinin, there is strong purifying selection acting on the gene, indicative of functional constraint.…”

Section: Hap_1 T G G T a G T T T G T A C C A G G C G G A T Gmentioning

confidence: 99%

Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

Mita

Culleton

Takahashi

et al. 2016

Antimicrob Agents Chemother

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The emergence and spread of artemisinin-resistant Plasmodium falciparum is of huge concern for the global effort toward malaria control and elimination. Artemisinin resistance, defined as a delayed time to parasite clearance following administration of artemisinin, is associated with mutations in the Pfkelch13 gene of resistant parasites. To date, as many as 60 nonsynonymous mutations have been identified in this gene, but whether these mutations have been selected by artemisinin usage or merely reflect natural polymorphism independent of selection is currently unknown. To clarify this, we sequenced the Pfkelch13 propeller domain in 581 isolates collected before (420 isolates) and after (161 isolates) the implementation of artemisinin combination therapies (ACTs), from various regions of endemicity worldwide. Nonsynonymous mutations were observed in 1% of parasites isolated prior to the introduction of ACTs. Frequencies of mutant isolates, nucleotide diversity, and haplotype diversity were significantly higher in the parasites isolated from populations exposed to artemisinin than in those from populations that had not been exposed to the drug. In the artemisinin-exposed population, a significant excess of dN compared to dS was observed, suggesting the presence of positive selection. In contrast, pairwise comparison of dN and dS and the McDonald and Kreitman test indicate that purifying selection acts on the Pfkelch13 propeller domain in populations not exposed to ACTs. These population genetic analyses reveal a low baseline of Pfkelch13 polymorphism, probably due to purifying selection in the absence of artemisinin selection. In contrast, various Pfkelch13 mutations have been selected under artemisinin pressure.

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“…Stable ART resistant strains of P. falciparum , have been obtained from infected patients while others have been manipulated to induce artemisinin resistance by subjecting parasites to increasing concentrations of DHA in vitro [ 22 , 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Induction of high tolerance to artemisinin by sub-lethal administration: A new in vitro model of P. falciparum

et al. 2018

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Artemisinin resistance is a major threat to malaria control efforts. Resistance is characterized by an increase in the Plasmodium falciparum parasite clearance half-life following treatment with artemisinin-based combination therapies (ACTs) and an increase in the percentage of surviving parasites. The remarkably short blood half-life of artemisinin derivatives may contribute to drug-resistance, possibly through factors including sub-lethal plasma concentrations and inadequate exposure. Here we selected for a new strain of artemisinin resistant parasites, termed the artemisinin resistant strain 1 (ARS1), by treating P. falciparum Palo Alto (PA) cultures with sub-lethal concentrations of dihydroartemisinin (DHA). The resistance phenotype was maintained for over 1 year through monthly maintenance treatments with low doses of 2.5 nM DHA. There was a moderate increase in the DHA IC50 in ARS1 when compared with parental strain PA after 72 h of drug exposure (from 0.68 nM to 2 nM DHA). In addition, ARS1 survived treatment physiologically relevant DHA concentrations (700 nM) observed in patients. Furthermore, we confirmed a lack of cross-resistance against a panel of antimalarials commonly used as partner drugs in ACTs. Finally, ARS1 did not contain Pfk13 propeller domain mutations associated with ART resistance in the Greater Mekong Region. With a stable growth rate, ARS1 represents a valuable tool for the development of new antimalarial compounds and studies to further elucidate the mechanisms of ART resistance.

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Fitness of artemisinin-resistantPlasmodium falciparum in vitro

Abstract: Artemisinin-resistant P. falciparum have a fitness advantage to survive and predominate in the population even in the face of infrequent exposure to artemisinin drugs.

Cited by 26 publications

References 35 publications

Molecular surveillance of putative drug resistance markers of antifolate and artemisinin among importedPlasmodium falciparumin Qatar

Molecular surveillance of putative drug resistance markers of antifolate and artemisinin among importedPlasmodium falciparumin Qatar

Little Polymorphism at the K13 Propeller Locus in Worldwide Plasmodium falciparum Populations Prior to the Introduction of Artemisinin Combination Therapies

Induction of high tolerance to artemisinin by sub-lethal administration: A new in vitro model of P. falciparum

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