A novel multiple-stage antimalarial agent that inhibits protein synthesis

Baragaña, Beatriz; Hallyburton, Irene; Lee, Marcus; Norcross, Neil R.; Grimaldi, Raffaella; Otto, Thomas D.; Proto, William R.; Blagborough, Andrew M.; Meister, Stephan; Wirjanata, Grennady; Ruecker, Andrea; Upton, Leanna M.; Abraham, Tara S.; Almeida, Mariana Justino de; Pradhan, Anupam; Porzelle, Achim; Martínez, María Santos; Bolscher, Judith M.; Woodland, Andrew; Norval, Suzanne; Zuccotto, Fabio; Thomas, John; Simeons, Frederick R. J.; Stojanovski, Laste; Osuna‐Cabello, Maria; Brock, Patrick M.; Churcher, Thomas S.; Sala, Katarzyna; Zakutansky, Sara E.; Jiménez-Dı́az, Marı́a Belén; Sanz, Laura M.; Riley, Jennifer; Basak, Rajshekhar; Campbell, Michael G.; Avery, Vicky M.; Sauerwein, Robert W.; Dechering, Koen J.; Noviyanti, Rintis; Campo, Brice; Frearson, Julie A.; Angulo-Barturen, Íñigo; Ferrer-Bazaga, Santiago; Gamo, Francisco Javier; Wyatt, Paul G.; Leroy, Didier; Siegl, P. K. S.; Delves, Michael J.; Kyle, Dennis E.; Wittlin, Sergio; Marfurt, Jutta; Price, Ric N.; Sinden, Robert E.; Winzeler, Elizabeth A.; Charman, Susan A.; Bebrevska, Lidiya; Gray, David W.; Campbell, Simon F.; Fairlamb, Alan H.; Willis, Paul; Rayner, Julian C.; Fidock, David A.; Read, Kevin D.; Gilbert, Ian H.

doi:10.1038/nature14451

Cited by 390 publications

(410 citation statements)

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“…While this confirms the fact that P. falciparum gametocytes are less sensitive than asexual stages to many antimalarial drugs, as has been previously shown for both earlystage (15) and late-stage (19) gametocytes, it also suggests that screening asexual-stage inhibitors for gametocytocidal activity increases the likelihood of identifying relevant compounds for drug development. This relationship is particularly useful given the current focus in antimalarial drug discovery and development on compounds with dual asexual and transmission-blocking activity (35)(36)(37)(38). The most active gametocytocidal compounds identified in our screening were from the MMV Malaria Box.…”

Section: Discussionmentioning

confidence: 99%

Luciferase-Based, High-Throughput Assay for Screening and Profiling Transmission-Blocking Compounds against Plasmodium falciparum Gametocytes

Lucantoni

Fidock

Avery

2016

Antimicrob Agents Chemother

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The discovery of new antimalarial drugs able to target both the asexual and gametocyte stages of Plasmodium falciparum is critical to the success of the malaria eradication campaign. We have developed and validated a robust, rapid, and cost-effective highthroughput reporter gene assay to identify compounds active against late-stage (stage IV and V) gametocytes. The assay, which is suitable for testing compound activity at incubation times up to 72 h, demonstrates excellent quality and reproducibility, with average Z= values of 0.85 ؎ 0.01. We used the assay to screen more than 10,000 compounds from three chemically diverse libraries. The screening outcomes highlighted the opportunity to use collections of compounds with known activity against the asexual stages of the parasites as a starting point for gametocytocidal activity detection in order to maximize the chances of identifying gametocytocidal compounds. This assay extends the capabilities of our previously reported luciferase assay, which tested compounds against early-stage gametocytes, and opens possibilities to profile the activities of gametocytocidal compounds over the entire course of gametocytogenesis.T he complex life cycle of the Plasmodium falciparum parasite, responsible for malaria, involves a human host, in which the intraerythrocytic asexual stages of the parasite cause the disease manifestations, and an anopheline mosquito vector, in which the parasite transmission stages genetically recombine and develop to successfully infect new human hosts. Parasite transmission to both the mosquito vector and the next human host rely on the sexual stage gametocytes. In P. falciparum, gametocytes emerge in low numbers from the asexual population and mature over a 10-to 12-day period, progressing through five morphologically distinct stages (I to V) (1). Mature stage V gametocytes can remain infective to the mosquito for an extended time, even if the asexual parasite population has been decreased by therapeutic drugs (2).The last 15 years have witnessed an unprecedented effort in the fight against malaria, with the deployment of large-scale interventions, including the distribution of artemisinin-based combination therapies (ACTs); targeted chemoprophylaxis of patient populations at particular risk, notably pregnant women and children under the age of 5 years; and vector control measures, including insecticide-treated bed nets. As a result, a 48% decrease in global malaria mortality rates was achieved between 2000 and 2015, and 16 countries have successfully eliminated malaria since 2010 (3). Although these impressive achievements have required a substantial economic outlay, it has become increasingly clear that an aggressive strategy aimed at malaria eradication is the only sustainable, albeit ambitious, goal in the long term (4). Achieving this ultimate goal is challenging, as malaria claims nearly 440,000 lives annually, and nearly half of the world's population is at risk of contracting the disease (3). The emergence of parasites resistant to current ...

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Section: Discussionmentioning

confidence: 99%

Luciferase-Based, High-Throughput Assay for Screening and Profiling Transmission-Blocking Compounds against Plasmodium falciparum Gametocytes

Lucantoni

Fidock

Avery

2016

Antimicrob Agents Chemother

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“…119–121). Among those, the eukaryotic elongation factor 2 (eEF2) and phenylalanine tRNA synthetase have been identified as targets of compounds active against all three parasite stages in humans 122,123 . With most of these targets, however, resistance has been flagged as a potential concern (Supplementary Table 2).…”

Section: Next-generation Antimalarialsmentioning

confidence: 99%

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

Blasco

Leroy

Fidock

2017

Nat Med

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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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“…We speculate that this difference may reflect the existence of conserved targets required for proliferation within a similar erythrocytic niche for diverse apicomplexan hemoprotozoan parasites and/or the close phylogenetic relatedness of Plasmodium and Babesia spp. Our results suggest that, with the discovery of novel antimalarial chemotypes at the blood stage (26)(27)(28)(29)(30), a substantial fraction is likely also to be babesiacidal and potentially lead to compounds to be repurposed for the treatment of babesiosis. The work discussed here has implications for chemotherapeutic strategies regarding malaria and babesiosis and should inspire more detailed investigation of the comparative biology of these parasites.…”

mentioning

confidence: 99%

Extensive Shared Chemosensitivity between Malaria and Babesiosis Blood-Stage Parasites

Paul

Moreira

Elsworth

et al. 2016

Antimicrob Agents Chemother

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The apicomplexan parasites that cause malaria and babesiosis invade and proliferate within erythrocytes. To assess the potential for common antiparasitic treatments, we measured the sensitivities of multiple species of Plasmodium and Babesia parasites to the chemically diverse collection of antimalarial compounds in the Malaria Box library. We observed that these parasites share sensitivities to a large fraction of the same inhibitors and we identified compounds with strong babesiacidal activity.T he apicomplexan phylum of eukaryotic microbial parasites is important in human and veterinary medicine. Apicomplexans cause malaria (Plasmodium spp.), babesiosis (Babesia spp.), toxoplasmosis (Toxoplasma gondii), and cryptosporidiosis (Cryptosporidium spp.), among other diseases. The Plasmodium and Babesia genera are relatively closely related among the apicomplexans (1) (last common ancestor, ϳ55 million years ago [2]) ( Fig. 1A) and share similar features in their biology, including mechanisms for host cell invasion and metabolism (3-6). Both Plasmodium and Babesia spp. are pathogenic during the stage of infection when parasites colonize host erythrocytes. Historically, drug development has focused more strongly on inhibitors for Plasmodium sp. parasites (7). Researchers have found that some antimalarial drugs also reduce proliferation of Babesia sp. parasites in erythrocytes as well (8, 9). The antimalarial atovaquone, a ubiquinone analog, is the preferred clinical treatment for human babesiosis in combination with azithromycin (10) and is used also in veterinary practice for babesiosis in dogs (11).A renewed focus on malaria eradication has led to the identification of an unprecedented number of bioactive compounds that block proliferation of Plasmodium falciparum in erythrocytes (12). In 2011, the nonprofit group Medicines for Malaria Venture (MMV) made available to the research community the Malaria Box, a collection of 400 chemically diverse, previously uncharacterized blood-stage antimalarials (13). Researchers have screened the antiparasitic activities of the Malaria Box compounds in nonerythrocytic host cells for the apicomplexans T. gondii, Cryptosporidium parvum, and Theileria annulata and identified a limited number of inhibitors (Ͻ3% of the library) active against each of these species (14-16). Here, we measured the susceptibilities of multiple blood-stage Plasmodium and Babesia parasite species to the Malaria Box compounds and found that erythrocyte-specific apicomplexans share considerable chemical sensitivities during the clinically relevant stages of parasitic infection.To determine the species-specific action of the Malaria Box compounds, we measured the chemical susceptibility of Plasmodium knowlesi in parallel with the reference species P. falciparum (13) (see Dataset S1 in the supplemental material). Endemic to macaque monkeys in southeast Asia and an emerging zoonosis in humans, P. knowlesi is distinguished from P. falciparum by its shorter blood-stage cell cycle and reduced rate of parasite mult...

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A novel multiple-stage antimalarial agent that inhibits protein synthesis

Cited by 390 publications

References 37 publications

Luciferase-Based, High-Throughput Assay for Screening and Profiling Transmission-Blocking Compounds against Plasmodium falciparum Gametocytes

Luciferase-Based, High-Throughput Assay for Screening and Profiling Transmission-Blocking Compounds against Plasmodium falciparum Gametocytes

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

Extensive Shared Chemosensitivity between Malaria and Babesiosis Blood-Stage Parasites

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