Repurposing of the Malaria Box for Babesia microti in mice identifies novel active scaffolds against piroplasmosis

Rizk, Mohamed Abdo; Baghdadi, Hanadi B.; El‒Sayed, Shimaa Abd El‒Salam; Eltaysh, Rasha; Igarashi, Ikuo

doi:10.1186/s13071-022-05430-4

Cited by 5 publications

(5 citation statements)

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“…In conclusion, additional studies to identify safe and efficacious anti-theilerial drugs for use in horses are urgently needed. Large-scale compound library screening experiments have enabled the identification of potentially efficacious drugs in some apicomplexan systems, and similar studies are needed for T. haneyi [ 35 , 36 , 37 , 38 , 39 , 40 ]. Furthermore, while several compounds have demonstrated in vitro efficacy against T. equi , very few have been tested against T. haneyi , or against either parasite in vivo [ 5 , 40 , 41 , 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Tulathromycin and Diclazuril Lack Efficacy against Theileria haneyi, but Tulathromycin Is Not Associated with Adverse Clinical Effects in Six Treated Adult Horses

et al. 2023

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Equine theileriosis, caused by Theileria haneyi and Theileria equi, leads to anemia, exercise intolerance, and occasionally, death. Theileriosis-free countries prohibit the importation of infected horses, resulting in significant costs for the equine industry. Imidocarb dipropionate is the only treatment for T. equi in the United States, but lacks efficacy against T. haneyi. The goal of this study was to assess the in vivo efficacy of tulathromycin and diclazuril against T. haneyi. Fourteen T. haneyi-infected horses were utilized. Six were treated with eight weekly 2.5 mg/kg doses of tulathromycin. Three were treated daily for eight weeks with 2.5 mg/kg diclazuril. Three were pre-treated with 0.5 mg/kg diclazuril daily for one month to determine whether low-dose diclazuril prevents infection. Following infection, the dose was increased to 2.5 mg/kg for eight weeks. Two infected horses remained untreated as controls. The horses were assessed via nested PCR, physical exams, complete blood counts, serum chemistry panels, and cytology. Tulathromycin and diclazuril failed to clear T. haneyi and the treated and control groups exhibited similar parasitemia and packed cell volume declines. To obtain additional safety data on tulathromycin use in adult horses, necropsy and histopathology were performed on tulathromycin-treated horses. No significant lesions were detected.

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Section: Discussionmentioning

confidence: 99%

Tulathromycin and Diclazuril Lack Efficacy against Theileria haneyi, but Tulathromycin Is Not Associated with Adverse Clinical Effects in Six Treated Adult Horses

et al. 2023

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“…The most common hematological complications of malaria and babesiosis are thrombocytopenia and anemia. Anemia is caused by a various of pathophysiologic mechanisms, including accelerated RBCs removal by the spleen, obligatory RBCs destruction at parasite schizogony, and ineffective erythropoiesis (Nie et al, 2021;Rizk et al, 2021;Rizk et al, 2022). Recent advancements have shown that a variety of cytokine dysregulations are indeed vital participants in inducing and accelerating the pathogenesis of hemolysis in malaria and babesiosis.…”

Section: Discussionmentioning

confidence: 99%

Characterization of anti-erythrocyte and anti-platelet antibodies in hemolytic anemia and thrombocytopenia induced by Plasmodium spp. and Babesiaspp. infection in mice

Zhou

Xie

Kawase

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionMalaria and Babesiosis are acute zoonotic disease that caused by infection with the parasite in the phylum Apicomplexa. Severe anemia and thrombocytopenia are the most common hematological complication of malaria and babesiosis. However, the mechanisms involved have not been elucidated, and only a few researches focus on the possible role of anti-erythrocyte and anti-platelet antibodies.MethodsIn this study, the Plasmodium yoelii, P. chabaudi, Babesia microti and B. rodhaini infected SCID and ICR mice. The parasitemia, survival rate, platelet count, anti-platelet antibodies, and the level of IFN-γ and interleukin (IL) -10 was tested after infection. Furthermore, the P. yoelii, P. chabaudi, B. rodhaini and B. microti infected ICR mice were treated with artesunate and diminaze, the development of the anti-erythrocyte and anti-platelet antibodies in chronic stage were examined. At last, the murine red blood cell and platelet membrane proteins probed with auto-antibodies induced by P. yoelii, P. chabaudi, B. rodhaini, and B. microti infection were characterized by proteomic analysis.Results and discussionThe high anti-platelet and anti-erythrocyte antibodies were detected in ICR mice after P. yoelii, P. chabaudi, B. rodhaini, and B. microti infection. Actin of murine erythrocyte and platelet is a common auto-antigen in Plasmodium and Babesia spp. infected mice. Our findings indicate that anti-erythrocyte and anti-platelet autoantibodies contribute to thrombocytopenia and anemia associated with Plasmodium spp. and Babesia spp. infection. This study will help to understand the mechanisms of malaria and babesiosis-related thrombocytopenia and hemolytic anemia.

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“…The mode of action for the antibabesial efficacy of MMV396693 is still unknown. However, our previous study (Rizk et al, 2022) suggested that both MMV396693 and ID might have a similar mode of action for inhibition Babesia parasite. The effectiveness of such compounds in combination therapy with other medication candidates can therefore be tested.…”

Section: Introductionmentioning

confidence: 92%

“…In this regard, several compounds recently demonstrated anti-piroplasm effects both in vitro and in vivo. For instance, the Malaria Box was used to screen for new potent antipiroplasm medications, such as 3-[(2-Hydroxyethyl)amino]-5-methylphenazin-5-ium "MMV396693," by testing it against the growth of several bovine Babesia and equine piroplasms in vitro and the B. microti parasite in vivo (Rizk et al, 2019;Rizk et al, 2022). The mode of action for the antibabesial efficacy of MMV396693 is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Antiparasitic activity of FLLL-32 against four Babesia species, B. bovis, B. bigemina, B. divergens and B. caballi, and one Theileria species, Theileria equi in vitro, and Babesia microti in mice

El-Sayed,

El-Alfy,

Baghdadi

et al. 2023

Front. Pharmacol.

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Introduction: FLLL-32, a synthetic analog of curcumin, is a potent inhibitor of STAT3’s constitutive activation in a variety of cancer cells, and its anticancer properties have been demonstrated both in vitro and in vivo. It is also suggested that it might have other pharmacological activities including activity against different parasites.Aim: This study therefore investigated the in vitro antiparasitic activity of FLLL-32 against four pathogenic Babesia species, B. bovis, B. bigemina, B. divergens, and B. caballi, and one Theileria species, Theileria equi. In vivo anti-Babesia microti activity of FLLL-32 was also evaluated in mice.Methods: The FLLL-32, in the growth inhibition assay with a concentration range (0.005–50 μM), was tested for it’s activity against these pathogens. The reverse transcription PCR (RT-PCR) assay was used to evaluate the possible effects of FLLL-32 treatment on the mRNA transcription of the target B. bovis genes including S-adenosylhomocysteine hydrolase and histone deacetylase.Results: The in vitro growth of B. bovis, B. bigemina, B. divergens, B. caballi, and T. equi was significantly inhibited in a dose-dependent manner (in all cases, p < 0.05). FLLL-32 exhibits the highest inhibitory effects on B. bovis growth in vitro, and it’s IC50 value against this species was 9.57 μM. The RT-PCR results showed that FLLL-32 inhibited the transcription of the B. bovis S-adenosylhomocysteine hydrolase gene. In vivo, the FLLL-32 showed significant inhibition (p < 0.05) of B. microti parasitemia in infected mice with results comparable to that of diminazene aceturate. Parasitemia level in B. microti-infected mice treated with FLLL-32 from day 12 post infection (pi) was reduced to reach zero level at day 16 pi when compared to the infected non-treated mice.Conclusion: The present study demonstrated the antibabesial properties of FLLL-32 and suggested it’s usage in the treatment of babesiosis especially when utilized in combination therapy with other antibabesial drugs.

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Repurposing of the Malaria Box for Babesia microti in mice identifies novel active scaffolds against piroplasmosis

Cited by 5 publications

References 50 publications

Tulathromycin and Diclazuril Lack Efficacy against Theileria haneyi, but Tulathromycin Is Not Associated with Adverse Clinical Effects in Six Treated Adult Horses

Tulathromycin and Diclazuril Lack Efficacy against Theileria haneyi, but Tulathromycin Is Not Associated with Adverse Clinical Effects in Six Treated Adult Horses

Characterization of anti-erythrocyte and anti-platelet antibodies in hemolytic anemia and thrombocytopenia induced by Plasmodium spp. and Babesiaspp. infection in mice

Antiparasitic activity of FLLL-32 against four Babesia species, B. bovis, B. bigemina, B. divergens and B. caballi, and one Theileria species, Theileria equi in vitro, and Babesia microti in mice

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