Targeting the Parasite to Suppress Malaria Transmission

Sinden, Robert E.

doi:10.1016/bs.apar.2016.09.004

Cited by 16 publications

(21 citation statements)

References 162 publications

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“…High-throughput screens have also been developed to identify compounds that act exclusively on the nonreplicating mature gametocytes to prevent their transmission, without exerting selective pressure on ABS parasites that could generate resistance 133,140–143 . Reducing the transmissibility of drug-resistant parasites in low-transmission settings is also an important argument supporting the addition of a single low dose of primaquine to current therapeutic regimens 144 .…”

Section: Can We Design Drugs That Are ‘Resistance Proof’?mentioning

confidence: 99%

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

Blasco

Leroy

Fidock

2017

Nat Med

440

419

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The global adoption of artemisinin-based combination therapies (ACTs) in the early 2000s heralded a new era in effectively treating drug-resistant Plasmodium falciparum malaria. However, several Southeast Asian countries have now reported the emergence of parasites that have decreased susceptibility to artemisinin (ART) derivatives and ACT partner drugs, resulting in increasing rates of treatment failures. Here we review recent advances in understanding how antimalarials act and how resistance develops, and discuss new strategies for effectively combatting resistance, optimizing treatment and advancing the global campaign to eliminate malaria.

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Section: Can We Design Drugs That Are ‘Resistance Proof’?mentioning

confidence: 99%

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

Blasco

Leroy

Fidock

2017

Nat Med

440

419

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“…Drug resistance and its spread is traditionally seen through the prism of disease, in the case of malaria the asexual replicative stages of the life cycle carried in blood circulation. However, resistance can only spread with passage of the parasite through the mosquito, a fundamental step in the Plasmodium lifecycle ( 13 ). Transmission of malaria parasites is solely mediated by non-pathogenic sexual stages called gametocytes.…”

Section: Introductionmentioning

confidence: 99%

“…Transmission of malaria parasites is solely mediated by non-pathogenic sexual stages called gametocytes. These gametocytes mature over the course of 10-12 days and are the only stages infectious to mosquitoes ( 13 ). During a mosquito blood feed, male and female gametocytes are taken up and activate in the mosquito midgut into male and female gametes.…”

Section: Introductionmentioning

confidence: 99%

Artemisinin-resistant malaria parasites show enhanced transmission to mosquitoes under drug pressure

Witmer

Dahalan

Delves

et al. 2020

Preprint

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25 Resistance to artemisinin combination therapy (ACT) in the Plasmodium falciparum 26 parasite is threatening to reverse recent gains in reducing global deaths from malaria. 27 Whilst resistance manifests as delayed asexual parasite clearance in patients following 28 ACT treatment, the phenotype can only spread geographically via the sexual cycle and 29 subsequent transmission through the mosquito. Artemisinin and its derivatives (such as 30 dihydroartemisinin, DHA) as well as killing the asexual parasite form are known to sterilize 31 male, sexual-stage gametes from activation. Whether resistant parasites overcome this 32 artemisinin-dependent sterilizing effect has not, however, been fully tested. Here, we 33 analysed five P. falciparum clinical isolates from the Greater Mekong Subregion, each of 34 which demonstrated delayed clinical clearance and carried known resistance-associated 35 polymorphisms in the Kelch13 gene (PfK13 var ). As well as demonstrating reduced 36 sensitivity to artemisinin-derivates in in vitro asexual growth assays, certain PfK13 var 37isolates also demonstrated a marked reduction in sensitivity to these drugs in an in vitro 38 male gamete activation assay compared to a sensitive control. Importantly, the same 39 reduction in sensitivity to DHA was observed when the most resistant isolate was assayed 40 by standard membrane feeding assays using Anopheles stephensi mosquitoes. These 41 results indicate that ACT use can favour resistant over sensitive parasite transmission. A 42 selective advantage for resistant parasite transmission could also favour acquisition of 43 further polymorphisms, such as mosquito host-specificity or antimalarial partner-drug 44 resistance in mixed infections. Favoured transmission of resistance under ACT coverage 45 could have profound implications for the spread of multidrug resistant malaria beyond 46 Southeast Asia. 47

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“…Improved malaria treatment and control has reduced morbidity and mortality worldwide by 40–50% since 2000 1 , due largely to highly effective artemisinin-based combination therapies and mosquito vector control measures 1,2 . An important strategy to further advance the malaria elimination agenda is to include transmission-blocking agents in combination therapies 3 . Such agents inhibit the development of parasite gametocytes (GAMs) that represent an alternative form of intra-erythrocytic development to the pathogenic asexual blood stage (ABS) parasites, and that mature over five stages 4 .…”

Section: Introductionmentioning

confidence: 99%

Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity

Vanaerschot

Lucantoni

et al. 2017

Nat Microbiol

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Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress P. berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR/Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 as a determinant of parasite resistance to HHQs. Hemoglobin and heme fractionation assays suggest a mode of action that results in reduced hemozoin levels and might involve inhibition of host hemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs including lumefantrine, confirming that HHQs have a different mode of action than other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.

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Targeting the Parasite to Suppress Malaria Transmission

Cited by 16 publications

References 162 publications

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic

Artemisinin-resistant malaria parasites show enhanced transmission to mosquitoes under drug pressure

Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity

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