In vitro screening of the open source Pathogen Box identifies novel compounds with profound activities against Neospora caninum

Müller, Joachim; Aguado, Adriana; Laleu, Benoît; Balmer, Vreni; Ritler, Dominic; Hemphill, Andrew

doi:10.1016/j.ijpara.2017.06.002

Cited by 29 publications

(31 citation statements)

References 33 publications

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“…Human foreskin fibroblasts (HFF) were maintained as described earlier (24,25). The B. besnoiti isolate Bb Lisbon was obtained, following published procedures (27), from a naturally occurring chronic case of bovine besnoitiosis.…”

Section: Host Cell Cultivation and Parasite Culturesmentioning

confidence: 99%

“…More recently, a series of ELQs were reported to exhibit promising in vitro activity against N. caninum tachyzoites (24). ELQ-400 treatment in mice experimentally infected with N. caninum tachyzoites lead to significantly reduced parasite burden (25). ELQ-334 treatment of N. caninum infected pregnant mice did not reduce the cerebral parasite burden in the dams, but inhibited vertical transmission and clinical signs in newborn pups and in the dams (24).…”

Section: Introductionmentioning

confidence: 99%

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Activities of Endochin-Like Quinolones Against in vitro Cultured Besnoitia besnoiti Tachyzoites

et al. 2020

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Endochin-like quinolones (ELQs) potently inhibit the proliferation of Plasmodium, Toxoplasma, Neospora, and Babesia by targeting the cytochrome b Qo and Qi sites and interfering with oxidative phosphorylation and pyrimidine biosynthesis. The activities of 14 different ELQs were assessed against B. besnoiti tachyzoites grown in human foreskin fibroblasts (HFF) by quantitative real time PCR. The values for 50% proliferation inhibition (IC50) of five ELQs were determined in a 3-days growth assay after an initial screen of 12 ELQs at 0.01, 0.1, and 1 µM. The IC50s of ELQ-121,-136, and-316 were 0.49, 2.36, and 7.97 nM, respectively. The IC50s of ELQs tested against B. besnoiti were higher than IC50s previously observed for P. falciparum and T. gondii. However, the B. besnoiti cytochrome b sequence and the predicted Qo and Qi ELQ binding sites in the Toxoplasma, Neospora, and Besnoitia cytochrome b are virtually identical, suggesting that the differences in ELQ susceptibility are not due to variations in the substrate binding sites. TEM of ELQ-treated parasites primarily demonstrated alterations within the parasite mitochondrion, profound thickening of the nuclear membrane, as well as increased vacuolization within the tachyzoite cytoplasm. Long-term treatment assays of intracellular B. besnoiti with ELQs for up to 20 days followed by the release of drug pressure caused a substantial delay in parasite growth and proliferation while ELQs were present, but parasite proliferation resumed days after ELQs were removed. Interestingly, structural alterations persisted after ELQ removal and parasite proliferation was slowed. These findings provide a basis for further in vivo studies of ELQs as therapeutic options against B. besnoiti infection.

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Section: Host Cell Cultivation and Parasite Culturesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activities of Endochin-Like Quinolones Against in vitro Cultured Besnoitia besnoiti Tachyzoites

et al. 2020

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“…Human foreskin fibroblasts (HFF), Vero cells and transgenic beta-galactosidase expressing Neospora caninum were cultivated as described [32].…”

Section: Cell Culturementioning

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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“…17 A study on Neospora caninum by Müller et al identified new compounds with profound activities. 18 A screening by Hennessey et al came across three new inhibitors with dual efficacy against Giardia lamblia and Cryptosporidium parvum. 19 PB screening on Plasmodium falciparum revealed one digestive vacuole-disrupting molecule.…”

Section: Introductionmentioning

confidence: 99%

<p><em>Leishmania donovani</em> Growth Inhibitors from Pathogen Box Compounds of Medicine for Malaria Venture</p>

Tadele¹,

Abay²,

Makonnen³

et al. 2020

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Introduction: Leishmaniasis is a collective term used to describe various pathological conditions caused by an obligate intracellular protozoan of the genus Leishmania. It is one of the neglected diseases and has been given minimal attention by drug discovery and development stakeholders to narrow the safety and efficacy gaps of the drugs currently used to treat leishmaniasis. The challenge is further exacerbated by the emergence of drug resistance by the parasites. Methods: Aiming to look for potential anti-leishmanial hits and leads, we screened Medicines for Malaria Venture (MMV) Pathogen Box compounds against clinically isolated Leishmania donovani strain. In this medium-throughput primary screening assay, the compounds were screened against promastigotes, and then against amastigote stages. Results: From the total 400 compounds screened, 35 compounds showed >50% inhibitory activity on promastigotes in the initial screen (1 μM). Out of these compounds, nine showed >70% inhibition, with median inhibitory concentration (IC 50 ) ranging from 12 to 491 nM using the anti-promastigote assay, and from 53 to 704 nM using the intracellular amastigote assay. Identified compounds demonstrated acceptable safety profiles on THP-1 cell lines and sheep red blood cells, and had appropriate physicochemical properties suitable for further drug development. Two compounds (MMV690102 and MMV688262) were identified as leads. The anti-tubercular agent MMV688262 (delamanid) showed a synergistic effect with amphotericin B, indicating the prospect of using this compound for combination therapy. Conclusion: The current study indicates the presence of additional hits which may hold promise as starting points for anti-leishmanial drug discovery and in-depth structure-activity relationship studies.

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In vitro screening of the open source Pathogen Box identifies novel compounds with profound activities against Neospora caninum

Cited by 29 publications

References 33 publications

Activities of Endochin-Like Quinolones Against in vitro Cultured Besnoitia besnoiti Tachyzoites

Activities of Endochin-Like Quinolones Against in vitro Cultured Besnoitia besnoiti Tachyzoites

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

<p><em>Leishmania donovani</em> Growth Inhibitors from Pathogen Box Compounds of Medicine for Malaria Venture</p>

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