<i>Plasmodium falciparum</i> resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination

Ouji, Manel; Augereau, Jean‐Michel; Paloque, Lucie; Benoit‐Vical, Françoise

doi:10.1051/parasite/2018021

Cited by 124 publications

(96 citation statements)

References 85 publications

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“…In most cases, malaria infections in humans are treated by artemisinin-based combination therapies, where 2 effective components with different modes of action and pharmacokinetic properties are combined. Emerging drug resistance makes it essential to search for new anti-malaria compounds and new targets in the parasite (Ouji, Augereau, Paloque, & Benoit-Vical, 2018) as no efficient vaccine for malaria is currently available.…”

Section: Introductionmentioning

confidence: 99%

Vital role forPlasmodium bergheiKinesin8B in axoneme assembly during male gamete formation and mosquito transmission

Depoix

Marques

Ferguson

et al. 2019

Cellular Microbiology

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Sexual development is an essential phase in the Plasmodium life cycle, where male gametogenesis is an unusual and extraordinarily rapid process. It produces 8 haploid motile microgametes, from a microgametocyte within 15 minutes. Its unique achievement lies in linking the assembly of 8 axonemes in the cytoplasm to the three rounds of intranuclear genome replication, forming motile microgametes, which are expelled in a process called exflagellation. Surprisingly little is known about the actors involved in these processes. We are interested in kinesins, molecular motors that could play potential roles in male gametogenesis. We have undertaken a functional characterization in Plasmodium berghei of kinesin-8B (PbKIN8B) expressed specifically in male gametocytes and gametes. By generating Pbkin8B-gfp parasites, we show that PbKIN8B is specifically expressed during male gametogenesis and is associated with the axoneme. We created a ΔPbkin8B knockout cell line and analysed the consequences of the absence of PbKIN8B on male gametogenesis. We show that the ability to produce sexually differentiated gametocytes is not affected in ΔPbkin8B parasites and that the 3 rounds of genome replication occur normally. Nevertheless, the development to free motile microgametes is halted and the life cycle is interrupted in vivo. Ultrastructural analysis revealed that intranuclear mitoses are unaffected whereas cytoplasmic microtubules, although assembled in doublets and elongated, fail to assemble in the normal axonemal '9+2' structure and become motile. Absence of a functional axoneme prevented microgamete assembly and release from the microgametocyte, severely reducing infection of the mosquito vector. This is the first functional study of a kinesin involved in male gametogenesis.These results reveal a previously unknown role for PbKIN8B in male gametogenesis, providing new insights into Plasmodium flagellar formation.

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Section: Introductionmentioning

confidence: 99%

Vital role forPlasmodium bergheiKinesin8B in axoneme assembly during male gamete formation and mosquito transmission

Depoix

Marques

Ferguson

et al. 2019

Cellular Microbiology

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“…The high DHA and ART in-vitro resistance did not significantly reflect in in-vivo therapeutic efficacy outcomes as earlier described [20]. It has been well documented that artemisinin resistance alone does not necessarily lead to treatment failures [38][39].…”

Section: Discussionmentioning

confidence: 58%

Drug sensitivity of Plasmodium falciparum field isolates to selected antimalarial drugs in Ghana using the in-vitro DAPI assay

Ofori

Kploanyi

Mensah

et al. 2020

Preprint

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Background: Malaria continues to be a major health issue globally with nine out of ten cases reported in Africa. Although the current artemisinin derived combination therapies in Ghana are still efficacious against the Plasmodium falciparum parasite, compounding evidence of artemisinin and amodiaquine resistance in the African region establish the need for a full, up-to-date understanding and monitoring of antimalarial resistance to provide evidence for planning control strategies.Methods: The study was cross-sectional and was conducted during the peak transmission seasons of 2015, 2016, and 2017 in two study sites located in different ecological zones of Ghana involving children aged 0.5-14 years presenting with symptomatic uncomplicated Plasmodium falciparum (Pf) malaria with parasitaemia greater than 1000 parasites/µl of blood. Using in vitro 4-,6-diamidino-2-phenylindole (DAPI) drug sensitivity assays, 328 Pf parasites collected were used to investigate susceptibility to five selected antimalarial drugs: chloroquine, amodiaquine, dihydroartemisinin, artesunate and mefloquine.Results: The geometric mean B (GMIC50) of five drugs against the parasites collected from Cape Coast were 9.6, 23.6, 9.1, 3.5 and 8.1nM for chloroquine, amodiaquine, artemisinin, artesunate, and mefloquine respectively in 2015. There was a 2 fold increase in the GMIC50 levels of all the drugs against the isolates collected in 2016 as compared to the 2015 data from Cape Coast .The a of the five drugs against the parasites collected from Cape Coast were significantly higher than those isolates collected from Begoro in 2016 and 2017 (P<0.001) . The chloroquine resistance ranged between 1.9% and 9.1% among isolates collected from Cape Coast but remained 0% in Begoro over the period. High amodiaquine resistance levels were recorded at both sites whilst that of artesunate resistance ranged between 4 and 10% over the study period.Conclusions: The study has assessed the antimalarial drug sensitivities of Ghanaian Pf isolates collected over 3 consecutive years. The parasites showed variable resistance levels to all the drugs used over the period. The study has demonstrated the continual return of chloroquine-sensitive parasites. The in vitro DAPI assay is a useful method for monitoring individual drugs used in combinations in Ghana for the generation of data on their sensitivities over time.

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“…However, ACT is known by its rapid parasite clearance more rapidly than other antimalarial such as quinine. In addition the drug target not only the late erythrocytic stage but also early stages of the parasites [37]. This shows the potent antimalarial property of Coartem ® targeting the blood stage parasite.…”

Section: Discussionmentioning

confidence: 90%

Efficacy of Artemisinin-lumefantrine for the treatment of uncomplicated malaria after more than a decade after its use in Kenya

Kishoyian

Njagi

Orinda

et al. 2020

Preprint

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Background: Plasmodium falciparum resistance to antimalarial drugs remains to be a major threat to the control of the disease globally. After the deployment of artemisinin-based combination therapy (ACT), there have been reports of reduced sensitivity of the drug to parasite clearance. In Kenya, artemisinin-lumefantrine (AL) is the recommended first-line drug in the treatment of uncomplicated malaria. This study sought to assess the efficacy of AL after its reintroduction in Kenya, a decade later. We assessed clinical and parasitological responses of children under five years in May and November 2015 in Chulaimbo sub-County, Kisumu, Kenya. Method: Patients of ≥6 and ≤60 months of age with confirmed Plasmodium falciparum mono-infection were enrolled in the study. The children were inpatient for close monitoring, they were treated with a standard dose of AL under supervision of a qualified nurse and followed up for 28 days. We monitored treatment adherence and responses. Efficacy of artemether lumefantrine on Plasmodium falciparum was determined.Results: Of the 90 patients enrolled, fourteen (14) were lost to follow-up, with 76 completing the study period. Seventy-five patients 75 (98.7%) cleared the parasitemia within 48 hours while one (1.3%) cleared on day 3. There was 100% clinical and parasitological parasite clearance. Conclusion: Artemisinin lumefantrine was found to be highly efficacious to plasmodium falciparum parasites in children aged ≥6 and ≤60 months. The results reported here indicate that the drug can be used to treat uncomplicated malaria in the study population. However, there is need for continued monitoring of its effectiveness in children and adults to counter the threat of resistance.

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Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination

Cited by 124 publications

References 85 publications

Vital role forPlasmodium bergheiKinesin8B in axoneme assembly during male gamete formation and mosquito transmission

Vital role forPlasmodium bergheiKinesin8B in axoneme assembly during male gamete formation and mosquito transmission

Drug sensitivity of Plasmodium falciparum field isolates to selected antimalarial drugs in Ghana using the in-vitro DAPI assay

Efficacy of Artemisinin-lumefantrine for the treatment of uncomplicated malaria after more than a decade after its use in Kenya

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