Evaluation of in vitro and in vivo inhibitory effects of fusidic acid on Babesia and Theileria parasites

Salama, Akram; AbouLaila, Mahmoud; Moussa, Ahmed; Nayel, Mohamed; Elsify, Ahmed; Terkawi, Mohamad Alaa; Hassan, Hany; Yokoyama, Naoki; Igarashi, Ikuo

doi:10.1016/j.vetpar.2012.08.022

Cited by 36 publications

(26 citation statements)

References 34 publications

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“…Some reports document 66% of Lyme patients, may also be co-infected with Babesia (Krause et al, 1996). Although drug regimen, mostly antibiotic combination therapies, inhibiting B. microti exist (Iseki et al, 2008; Salama et al, 2012; Ueno et al, 2013), these chemotherapeutics either require high dosage to be effective or have undesirable side effects (Galay et al, 2011; Munkhjargal et al, 2012; Salama et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Bumped kinase inhibitor prohibits egression in Babesia bovis

Pedroni

Vidadala

Choi

et al. 2016

Veterinary Parasitology

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Babesiosis is a global zoonotic disease acquired by the bite of a Babesia-infected Ixodes tick or through blood transfusion with clinical relevance affecting humans and animals. In this study, we evaluated a series of small molecule compounds that have previously been shown to target specific apicomplexan enzymes in Plasmodium, Toxoplasma and Cryptosporidium. The compounds, bumped kinase inhibitors (BKIs), have strong therapeutic potential targeting apicomplexa-specific calcium dependent protein kinases (CDPKs). We investigated if BKIs also show inhibitory activities against piroplasms such as Babesia. Using a subset of BKIs that have promising inhibitory activities to Plasmodium and Toxoplasma, we determined that their actions ranged from 100% and no inhibition against B. bovis blood stages. One specific BKI, RM-1-152, showed complete inhibition against B. bovis within 48h and was the only BKI that showed noticeable phenotypic changes to the parasites. Focusing our study on this BKI, we further demonstrated that RM-1-152 has Babesia-static activity and involves the prohibition of merozoite egress while replication and re-invasion of host cells are unaffected. The distinct, abnormal phenotype induced by RM-1-152 suggests that this BKI can be used to investigate less studied cellular processes such as egression in piroplasm.

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Section: Introductionmentioning

confidence: 99%

Bumped kinase inhibitor prohibits egression in Babesia bovis

Pedroni

Vidadala

Choi

et al. 2016

Veterinary Parasitology

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“…ATV was the most effective drug in this study, as its IC 50 value was lower than those of LFN and Di (control drug). Moreover, ATV IC 50 was lower than those of Epoxomicin [1], EGCG [2], Fusidic acid [31] and Trisubstitute pyrrole [21] which were recently evaluated as anti- B. bovis compounds. However, ATV inhibitory effect was similar to Apicidin (IC 50 = 7.1 n g/m l ) [24].…”

Section: Discussionmentioning

confidence: 99%

“…Effect of DHODH inhibitors on B. bovis growth in vitro : The effects of DHODH inhibitors on B. bovis growth were evaluated using 96-well plate (Nunc), according to the procedure previously described [31]. Atovaquone (ATV), brequinar (Breq), leflunomide (LFN) and 7-hydroxy-5- [1, 2, 4] triazolo [1, 5, a] pyrimidine (TAZ) were dissolved in dimethyl sulfoxide (DMSO) (Wako) as stock solutions, while diminazene aceturate (Di), the control drug, was prepared in distilled water.…”

Section: Methodsmentioning

confidence: 99%

<i>Babesia bovis</i> Dihydroorotate Dehydrogenase (BboDHODH) is a Novel Molecular Target of Drug for Bovine Babesiosis

Kamyingkird

Cao

Masatani

et al. 2014

The Journal of Veterinary Medical Science

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The emergence of drug resistance and adverse side effects of current bovine babesiosis treatment suggest that the search of new drug targets and development of safer and effective compounds are required. This study focuses on dihydroorotate dehydrogenase (DHODH), the fourth enzyme of pyrimidine biosynthesis pathway as a potential drug target for bovine babesiosis. Recombinant Babesia bovis DHODH protein (rBboDHODH) was produced in Escherichia coli and used for characterization and measurement of enzymatic activity. Furthermore, the effects of DHODH inhibitors were evaluated in vitro. The recombinant B. bovis DHODH histidine fusion protein (rBboDHODH) had 42.4-kDa molecular weight and exhibited a specific activity of 475.7 ± 245 Unit/mg, a Km = 276.2 µM for L-dihydroorotate and a Km= 94.41 µM for decylubiquinone. A 44-kDa band of native BboDHODH was detected by Western blot analysis and found in parasites mitochondria using a confocal microscope. Among DHODH inhibitors, atovaquone (ATV) and leflunomide (LFN) significantly inhibited the activity of rBboDHODH as well as the growth of B. bovis in vitro. The half maximal inhibitory concentration (IC50) of ATV and LFN was 2.38 ± 0.53 nM and 52.41 ± 11.47 µM, respectively. These results suggest that BboDHODH might be a novel target for development of new drug for treatment of B. bovis infection.

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“…Organellar EF-Gs are also candidate targets for drug intervention against apicomplexan parasites. The steroid antibiotic fusidic acid shows an anti-parasiticidal activity on P. falciparum blood stages (Johnson et al 2011) as well as on veterinary parasites Babesia and Theileria (Salama et al 2012). The drug acts by locking EF-G.GDP onto the ribosome after translocation thus inhibiting the next round of elongation (Willie et al 1975;Ticu et al 2009).…”

Section: Translation Components As Targets For Drug Intervention Agaimentioning

confidence: 99%

Translation in Mitochondria and Apicoplasts of Apicomplexan Parasites

Gupta

Haider

Vaishya

et al. 2013

Translation in Mitochondria and Other Organelles

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Protozoan parasites of the phylum apicomplexa are the causal organisms for several important infectious diseases. They contain three cellular compartments -the cytoplasm, mitochondrion, and the relic plastid called the apicoplast, where active translation takes place. Early investigations of the components and activities of the translation machinery in parasite organelles have provided evidence for intriguing variations from other systems. Understanding these mechanisms also offers novel possibilities for drug intervention. In this article, we discuss the translation machinery in the apicoplast and mitochondrion of the apicomplexan cell, with emphasis on current knowledge from Plasmodium and Toxoplasma.

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Evaluation of in vitro and in vivo inhibitory effects of fusidic acid on Babesia and Theileria parasites

Cited by 36 publications

References 34 publications

Bumped kinase inhibitor prohibits egression in Babesia bovis

Bumped kinase inhibitor prohibits egression in Babesia bovis

<i>Babesia bovis</i> Dihydroorotate Dehydrogenase (BboDHODH) is a Novel Molecular Target of Drug for Bovine Babesiosis

Translation in Mitochondria and Apicoplasts of Apicomplexan Parasites

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