Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-08-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320719300454 |
| _version_ | 1818131153459085312 |
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| author | Aruna Shrestha Kayode K. Ojo Florian Koston Bärbel Ruttkowski Rama S.R. Vidadala Carlie S. Dorr Edelmar D. Navaluna Grant R. Whitman Kayleigh F. Barrett Lynn K. Barrett Matthew A. Hulverson Ryan Choi Samantha A. Michaels Dustin J. Maly Andrew Hemphill Wesley C. Van Voorhis Anja Joachim |
| author_facet | Aruna Shrestha Kayode K. Ojo Florian Koston Bärbel Ruttkowski Rama S.R. Vidadala Carlie S. Dorr Edelmar D. Navaluna Grant R. Whitman Kayleigh F. Barrett Lynn K. Barrett Matthew A. Hulverson Ryan Choi Samantha A. Michaels Dustin J. Maly Andrew Hemphill Wesley C. Van Voorhis Anja Joachim |
| author_sort | Aruna Shrestha |
| collection | DOAJ |
| description | 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. Keywords: Cystoisosporosis, CsCDPK1, Efficacy, Pharmacokinetics, Safety |
| first_indexed | 2024-12-11T08:16:24Z |
| format | Article |
| id | doaj.art-a1a719e47d4b426fa88a60a6c691ec34 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-12-11T08:16:24Z |
| publishDate | 2019-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-a1a719e47d4b426fa88a60a6c691ec342022-12-22T01:14:46ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072019-08-0110919Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitroAruna Shrestha0Kayode K. Ojo1Florian Koston2Bärbel Ruttkowski3Rama S.R. Vidadala4Carlie S. Dorr5Edelmar D. Navaluna6Grant R. Whitman7Kayleigh F. Barrett8Lynn K. Barrett9Matthew A. Hulverson10Ryan Choi11Samantha A. Michaels12Dustin J. Maly13Andrew Hemphill14Wesley C. Van Voorhis15Anja Joachim16Institute of Parasitology, Department of Pathobiology, University of Veterinary Medicine, Veterinärplatz 1, A-1210, Vienna, Austria; Corresponding author. Veterinärplatz 1, A-1210, Vienna, Austria.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, USAInstitute of Parasitology, Department of Pathobiology, University of Veterinary Medicine, Veterinärplatz 1, A-1210, Vienna, AustriaInstitute of Parasitology, Department of Pathobiology, University of Veterinary Medicine, Veterinärplatz 1, A-1210, Vienna, AustriaDepartment of Chemistry, University of Washington, Seattle, WA, 98195, USACenter for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USACenter for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USACenter for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USACenter for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USACenter for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USACenter for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USACenter for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USACenter for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USADepartment of Chemistry, University of Washington, Seattle, WA, 98195, USAInstitute of Parasitology, Vetsuisse Faculty, University of Bern, Länggasstrasse 122, 3012, Bern, SwitzerlandCenter for Emerging and Reemerging Infectious Diseases, Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, 750 Republican Street, Seattle, WA, 98109, USAInstitute of Parasitology, Department of Pathobiology, University of Veterinary Medicine, Veterinärplatz 1, A-1210, Vienna, AustriaCystoisosporosis 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. Keywords: Cystoisosporosis, CsCDPK1, Efficacy, Pharmacokinetics, Safetyhttp://www.sciencedirect.com/science/article/pii/S2211320719300454 |
| spellingShingle | Aruna Shrestha Kayode K. Ojo Florian Koston Bärbel Ruttkowski Rama S.R. Vidadala Carlie S. Dorr Edelmar D. Navaluna Grant R. Whitman Kayleigh F. Barrett Lynn K. Barrett Matthew A. Hulverson Ryan Choi Samantha A. Michaels Dustin J. Maly Andrew Hemphill Wesley C. Van Voorhis Anja Joachim Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro International Journal for Parasitology: Drugs and Drug Resistance |
| title | Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro |
| title_full | Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro |
| title_fullStr | Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro |
| title_full_unstemmed | Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro |
| title_short | Bumped kinase inhibitor 1369 is effective against Cystoisospora suis in vivo and in vitro |
| title_sort | bumped kinase inhibitor 1369 is effective against cystoisospora suis in vivo and in vitro |
| url | http://www.sciencedirect.com/science/article/pii/S2211320719300454 |
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