The Impact of BKI-1294 Therapy in Mice Infected With the Apicomplexan Parasite Neospora caninum and Re-infected During Pregnancy

Winzer, Pablo; Imhof, Dennis; Anghel, Nicoleta; Ritler, Dominic; Müller, Joachim; Boubaker, Ghalia; Aguado‐Martínez, Adriana; Ortega-Mora, Luis-Miguel; Ojo, Kayode K.; VanVoorhis, Wesley C.; Hemphill, Andrew

doi:10.3389/fvets.2020.587570

Cited by 9 publications

(6 citation statements)

References 58 publications

(73 reference statements)

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“…In terms of drug efficacy in vivo, a parasitostatic effect could be an advantage. If the parasite is kept at a subclinical level, the antigenic stimulus might still be sufficiently high to provide a sustained immune response, potentially preventing reinfection after recovering from the acute stage, as it has been postulated for other compounds, such as bumped kinase inhibitors (BKIs) [45,46]. We thus assessed the efficacy of RMB060 in the pregnant T. gondii ShSp1 oocyst infection model.…”

Section: Discussionmentioning

confidence: 99%

“…Human foreskin fibroblasts (HFF; PCS-201-010 TM ) were cultured as described [45]. Tachyzoites of T. gondii β-gal (Tg-β-gal) constitutively expressing β-galactosidase were kindly provided by Prof. David Sibley, Washington University, St. Louis, USA; the T. gondii Me49 (TgMe49) strain was obtained from Dr. Furio Spano, Istituto Superiore di Sanita, Rome, Italy; a low-passage number Spanish T. gondii Pig isolate (TgPgSp1) was obtained from SALUVET-Innova (ETCU-UCM), Madrid [48].…”

Section: Host Cells and Parasitesmentioning

confidence: 99%

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Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii In Vitro and in Pregnant Mice Infected with T. gondii Oocysts

et al. 2021

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The quinolone decoquinate (DCQ) is widely used in veterinary practice for the treatment of bacterial and parasitic infections, most notably, coccidiosis in poultry and in ruminants. We have investigated the effects of treatment of Toxoplasma gondii in infected human foreskin fibroblasts (HFF) with DCQ. This induced distinct alterations in the parasite mitochondrion within 24 h, which persisted even after long-term (500 nM, 52 days) treatment, although there was no parasiticidal effect. Based on the low half-maximal effective concentration (IC50) of 1.1 nM and the high selectivity index of >5000, the efficacy of oral treatment of pregnant mice experimentally infected with T. gondii oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than T. gondii infection alone, and did not prevent vertical transmission. Thus, three quinoline-O-carbamate derivatives of DCQ, anticipated to have better physicochemical properties than DCQ, were assessed in vitro. One such compound, RMB060, displayed an exceedingly low IC50 of 0.07 nM, when applied concomitantly with the infection of host cells and had no impact on HFF viability at 10 µM. As was the case for DCQ, RMB060 treatment resulted in the alteration of the mitochondrial matrix and loss of cristae, but the changes became apparent at just 6 h after the commencement of treatment. After 48 h, RMB060 induced the expression of the bradyzoite antigen BAG1, but TEM did not reveal any other features reminiscent of bradyzoites. The exposure of infected cultures to 300 nM RMB060 for 52 days did not result in the complete killing of all tachyzoites, although mitochondria remained ultrastructurally damaged and there was a slower proliferation rate. The treatment of mice infected with T. gondii oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.

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Section: Discussionmentioning

confidence: 99%

Section: Host Cells and Parasitesmentioning

confidence: 99%

Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii In Vitro and in Pregnant Mice Infected with T. gondii Oocysts

et al. 2021

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“…A combined vaccine-linked chemotherapy strategy had been tested previously using a sublethal dose of N. caninum tachyzoites, which induced a high level protection of both dams and offspring against re-infection. However, treatment of vaccinated mice with another CDPK1-inhibitor, BKI-1294, prior to re-infection had detrimental effects and resulted in increased vertical transmission upon re-challenge of these mice ( 56 ). This effect was attributed to a potential inactivation of the live vaccine by the drug itself.…”

Section: Discussionmentioning

confidence: 99%

Vaccine-Linked Chemotherapy Approach: Additive Effects of Combining the Listeria monocytogenes-Based Vaccine Lm3Dx_NcSAG1 With the Bumped Kinase Inhibitor BKI-1748 Against Neospora caninum Infection in Mice

et al. 2022

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The apicomplexan parasite Neospora (N.) caninum causes neosporosis in numerous host species. There is no marketed vaccine and no licensed drug for the prevention and/or treatment of neosporosis. Vaccine development against this parasite has encountered significant obstacles, probably due to pregnancy-induced immunomodulation hampering efficacy, which has stimulated the search for potential drug therapies that could be applied to limit the effects of neosporosis in dams as well as in offspring. We here investigated, in a pregnant neosporosis mouse model, the safety and efficacy of a combined vaccination-drug treatment approach. Mice were vaccinated intramuscularly with 1 × 107 CFU of our recently generated Listeria (L.) monocytogenes vaccine vector expressing the major N. caninum tachyzoite surface antigen NcSAG1 (Lm3Dx_SAG1). Following mating and experimental subcutaneous infection with 1 × 105N. caninum (NcSpain-7) tachyzoites on day 7 of pregnancy, drug treatments were initiated using the bumped kinase inhibitor BKI-1748 at 20 mg/kg/day for 5 days. In parallel, other experimental groups were either just vaccinated or only treated. Dams and offspring were followed-up until day 25 post-partum, after which all mice were euthanized. None of the treatments induced adverse effects and neither of the treatments affected fertility or litter sizes. Cerebral infection in dams as assessed by real-time PCR was significantly reduced in the vaccinated and BKI-1748 treated groups, but was not reduced significantly in the group receiving the combination. However, in non-pregnant mice, all three treatment groups exhibited significantly reduced parasite burdens. Both, vaccination as well BKI-1748 as single treatment increased pup survival to 44 and 48%, respectively, while the combination treatment led to survival of 86% of all pups. Vertical transmission in the combination group was 23% compared to 46 and 50% in the groups receiving only BKI-treatment or the vaccine, respectively. In the dams, IgG titers were significantly reduced in all treatment groups compared to the untreated control, while in non-pregnant mice, IgG titers were reduced only in the group receiving the vaccine. Overall, vaccine-linked chemotherapy was more efficacious than vaccination or drug treatment alone and should be considered for further evaluation in a more relevant experimental model.

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“…Human foreskin fibroblasts (HFF; PCS-201-010 TM ) were cultured as described [45]. Tachyzoites of T. gondii β-gal (Tg-β-gal) constitutively expressing β-galactosidase were kindly provided by Prof. David Sibley, Washington University, St. Louis, USA, the T. gondii Me49 (TgMe49) strain was obtained from Dr. Furio Spano, Istituto Superiore di Sanita, Rome, Italy, and a low-passage number Spanish T. gondii Pig isolate (TgPgSp1) was obtained from SALUVET-Innova (ETCU-UCM), Madrid [48].…”

Section: Host Cells and Parasitesmentioning

confidence: 99%

Comparative Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii in vitro and in Pregnant Mice Infected with T. gondii Oocysts

Ramseier¹,

Imhof²,

Anghel³

et al. 2021

Preprint

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The quinolone decoquinate (DCQ) is widely used in veterinary practice for the treatment of bacte-rial and parasitic infections, most notably coccidiosis in poultry and in ruminants. We have in-vestigated the effects of treatment of Toxoplasma gondii in infected human foreskin fibroblasts (HFF) with DCQ. It induced distinct alterations in the parasite mitochondrion within 24h, which persisted even after long-term (500 nM, 52 days) treatment, although there was no parasiticidal effect. Based on the low half-maximal effective concentration (IC50) of 1.1 nM and the high selec-tivity index of >5000, the efficacy of oral treatment of pregnant mice experimentally infected with T. gondii oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than T. gondii infection alone, and did not prevent vertical transmission. Thus, three quinoline-O-carbamate derivatives of DCQ antici-pated to have better physicochemical properties than DCQ were assessed in vitro. One such com-pound RMB060 displayed an exceedingly low IC50 of 0.07 nM when applied concomitantly with infection of host cells and had no impact on HFF viability at 10 µM. As was the case for DCQ, RMB060 treatment resulted in alteration of the mitochondrial matrix and loss of cristae, but the changes became apparent at just 6h after commencement of treatment. After 48h, RMB060 induced the expression of the bradyzoite antigen BAG1, but TEM did not reveal any other features remi-niscent of bradyzoites. Exposure of infected cultures to 300 nM RMB060 for 52 days did not re-sult in complete killing of all tachyzoites, although mitochondria remained ultrastructurally damaged and there was a slower proliferation rate. Treatment of mice infected with T. gondii oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.

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The Impact of BKI-1294 Therapy in Mice Infected With the Apicomplexan Parasite Neospora caninum and Re-infected During Pregnancy

Cited by 9 publications

References 58 publications

Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii In Vitro and in Pregnant Mice Infected with T. gondii Oocysts

Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii In Vitro and in Pregnant Mice Infected with T. gondii Oocysts

Vaccine-Linked Chemotherapy Approach: Additive Effects of Combining the Listeria monocytogenes-Based Vaccine Lm3Dx_NcSAG1 With the Bumped Kinase Inhibitor BKI-1748 Against Neospora caninum Infection in Mice

Comparative Assessment of the Activity of Decoquinate and Its Quinoline-<em>O</em>-Carbamate Derivatives against <em>Toxoplasma gondii</em> <em>in vitro</em> and in Pregnant Mice Infected with <em>T. gondii </em>Oocysts

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