<i>In Vitro</i>
            Screening of the Open-Source Medicines for Malaria Venture Malaria Box Reveals Novel Compounds with Profound Activities against Theileria annulata Schizonts

Hostettler, Isabel C.; Müller, Joachim; Hemphill, Andrew

doi:10.1128/aac.02801-15

Cited by 15 publications

(25 citation statements)

References 35 publications

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“…Imidocarb exhibited IC 50 values of 230 to 690 nM against the Babesia parasite species, and we observed IC 50 (13). The breadth of babesiacidal Malaria Box inhibitors is striking in relation to the comparatively few Malaria Box inhibitors reportedly active against nonerythrocyte apicomplexans, such as T. gondii, C. parvum, and T. annulata (14)(15)(16). 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.…”

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confidence: 75%

“…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)(15)(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.…”

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confidence: 99%

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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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confidence: 75%

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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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“…Currently, the Malaria Box has been screened against a number of P. falciparum targets and multiple developmental stages (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), as well as other pathogens (20)(21)(22)(23)(24)(25)(26)(27)(28)(29). These studies have identified compounds in the Malaria Box with efficacy against specific metabolic processes, such as the thioredoxin system (9), isoprenoid biosynthesis (14,30), and aminopeptidases (11), as well as protein translation (10) and beta-hematin formation (17).…”

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confidence: 99%

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

Allman

Painter

Jasmeet

et al. 2016

Antimicrob Agents Chemother

123

184

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The threat of widespread drug resistance to frontline antimalarials has renewed the urgency for identifying inexpensive chemotherapeutic compounds that are effective against Plasmodium falciparum, the parasite species responsible for the greatest number of malaria-related deaths worldwide. To aid in the fight against malaria, a recent extensive screening campaign has generated thousands of lead compounds with low micromolar activity against blood stage parasites. A subset of these leads has been compiled by the Medicines for Malaria Venture (MMV) into a collection of structurally diverse compounds known as the MMV Malaria Box. Currently, little is known regarding the activity of these Malaria Box compounds on parasite metabolism during intraerythrocytic development, and a majority of the targets for these drugs have yet to be defined. Here we interrogated the in vitro metabolic effects of 189 drugs (including 169 of the drug-like compounds from the Malaria Box) using ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). The resulting metabolic fingerprints provide information on the parasite biochemical pathways affected by pharmacologic intervention and offer a critical blueprint for selecting and advancing lead compounds as next-generation antimalarial drugs. Our results reveal several major classes of metabolic disruption, which allow us to predict the mode of action (MoA) for many of the Malaria Box compounds. We anticipate that future combination therapies will be greatly informed by these results, allowing for the selection of appropriate drug combinations that simultaneously target multiple metabolic pathways, with the aim of eliminating malaria and forestalling the expansion of drug-resistant parasites in the field.

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“…An in vitro screening of 390 MMV Malariabox compounds against Neospora caninum yielded in the identification of 28 compounds with specific activity against N. caninum. Nine of these compounds were also effective against Theileria annulata [18], another apicomplexan parasite affecting cattle, transmitted by ticks. Of these nine compounds, the most effective is compound (1) or MMV665941, a triphenyl-methanol closely related to crystal violet.…”

Section: Discussionmentioning

confidence: 99%

“…have not been extensively covered. Thus, we have screened the Malaria box against N. caninum and T. annulata in separate studies, and the results of the screening against T. annulata were published elsewhere [18]. Here, we present the results of a differential screening of the Malaria Box against N. caninum and their host cells used for in vitro maintenance of these parasites.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Activities of MMV Malaria Box Compounds against the Apicomplexan Parasite Neospora caninum, the Causative Agent of Neosporosis in Animals

et al. 2020

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(1) Background: Neospora caninum is a major cause of abortion in cattle and represents a veterinary health problem of great economic significance. In order to identify novel chemotherapeutic agents for the treatment of neosporosis, the Medicines for Malaria Venture (MMV) Malaria Box, a unique collection of anti-malarial compounds, were screened against N. caninum tachyzoites, and the most efficient compounds were characterized in more detail. (2) Methods: A N. caninum beta-galactosidase reporter strain grown in human foreskin fibroblasts was treated with 390 compounds from the MMV Malaria Box. The IC50s of nine compounds were determined, all of which had been previously been shown to be active against another apicomplexan parasite, Theileria annulata. The effects of three of these compounds on the ultrastructure of N. caninum tachyzoites were further investigated by transmission electron microscopy at different timepoints after initiation of drug treatment. (3) Results: Five MMV Malaria Box compounds exhibited promising IC50s below 0.2 µM. The compound with the lowest IC50, namely 25 nM, was MMV665941. This compound and two others, MMV665807 and MMV009085, specifically induced distinct alterations in the tachyzoites. More specifically, aberrant structural changes were first observed in the parasite mitochondrion, and subsequently progressed to other cytoplasmic compartments of the tachyzoites. The pharmacokinetic (PK) data obtained in mice suggest that treatment with MMV665941 could be potentially useful for further in vivo studies. (4) Conclusions: We have identified five novel compounds with promising activities against N. caninum, the effects of three of these compounds were studies by transmission electron microscopy (TEM). Their modes of action are unknown and require further investigation.

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In Vitro Screening of the Open-Source Medicines for Malaria Venture Malaria Box Reveals Novel Compounds with Profound Activities against Theileria annulata Schizonts

Cited by 15 publications

References 35 publications

Extensive Shared Chemosensitivity between Malaria and Babesiosis Blood-Stage Parasites

Extensive Shared Chemosensitivity between Malaria and Babesiosis Blood-Stage Parasites

Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways

In Vitro Activities of MMV Malaria Box Compounds against the Apicomplexan Parasite Neospora caninum, the Causative Agent of Neosporosis in Animals

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