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Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro.
Journal article

Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro.

  • Shrestha A Institute of Parasitology, Department of Pathobiology, University of Veterinary Medicine, Veterinärplatz 1, A-1210, Vienna, Austria. Electronic address: Aruna.Shrestha@vetmeduni.ac.at.
  • Ojo KK Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Koston F Institute of Parasitology, Department of Pathobiology, University of Veterinary Medicine, Veterinärplatz 1, A-1210, Vienna, Austria.
  • Ruttkowski B Institute of Parasitology, Department of Pathobiology, University of Veterinary Medicine, Veterinärplatz 1, A-1210, Vienna, Austria.
  • Vidadala RSR Department of Chemistry, University of Washington, Seattle, WA, 98195, USA.
  • Dorr CS Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Navaluna ED Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Whitman GR Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Barrett KF Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Barrett LK Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Hulverson MA Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Choi R Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Michaels SA Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Maly DJ Department of Chemistry, University of Washington, Seattle, WA, 98195, USA.
  • Hemphill A Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggasstrasse 122, 3012, Bern, Switzerland.
  • Van Voorhis WC Center for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USA.
  • Joachim A Institute of Parasitology, Department of Pathobiology, University of Veterinary Medicine, Veterinärplatz 1, A-1210, Vienna, Austria.
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  • 2019-04-09
Published in:
  • International journal for parasitology. Drugs and drug resistance. - 2019
CsCDPK1
Cystoisosporosis
Efficacy
Pharmacokinetics
Safety
Animals
Antiprotozoal Agents
Coccidiosis
Female
Male
Protein Kinase Inhibitors
Protein Kinases
Protozoan Proteins
Sarcocystidae
Swine
Swine Diseases
English Cystoisosporosis is a leading diarrheal disease in suckling piglets. With the confirmation of resistance against the only available drug toltrazuril, there is a substantial need for novel therapeutics to combat the infection and its negative effects on animal health. In closely related apicomplexan species, bumped kinase inhibitors (BKIs) targeting calcium-dependent protein kinase 1 (CDPK1) were shown to be effective in inhibiting host-cell invasion and parasite growth. Therefore, the gene coding for Cystoisospora suis CDPK1 (CsCDPK1) was identified and cloned to investigate activity and thermal stabilization of the recombinant CsCDPK1 enzyme by BKI 1369. In this comprehensive study, the efficacy, safety and pharmacokinetics of BKI 1369 in piglets experimentally infected with Cystoisospora suis (toltrazuril-sensitive, Wien-I and toltrazuril-resistant, Holland-I strains) were determined in vivo and in vitro using an established animal infection model and cell culture, respectively. BKI 1369 inhibited merozoite proliferation in intestinal porcine epithelial cells-1 (IPEC-1) by at least 50% at a concentration of 40 nM, and proliferation was almost completely inhibited (>95%) at 200 nM. Nonetheless, exposure of infected cultures to 200 nM BKI 1369 for five days did not induce structural alterations in surviving merozoites as confirmed by transmission electron microscopy. Five-day treatment with BKI 1369 (10 mg/kg BW twice a day) effectively suppressed oocyst excretion and diarrhea and improved body weight gains in treated piglets without obvious side effects for both toltrazuril-sensitive, Wien-I and resistant, Holland-I C. suis strains. The plasma concentration of BKI 1369 in piglets increased to 11.7 μM during treatment, suggesting constant drug accumulation and exposure of parasites to the drug. Therefore, oral applications of BKI 1369 could potentially be a therapeutic alternative against porcine cystoisosporosis. For use in pigs, future studies on BKI 1369 should be directed towards ease of drug handling and minimizing treatment frequencies.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/157110
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