Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy.

Sánchez-Sánchez, Roberto; Ferre, Ignacio; Re, Michela; Ramos, Juan José; Regidor-Cerrillo, Javier; Pizarro Díaz, Manuel; González-Huecas, Marta; Tabanera, Enrique; Benavides, Julio; Hemphill, Andrew; Hulverson, Matthew A; Barrett, Lynn K; Choi, Ryan; Whitman, Grant R; Ojo, Kayode K; Van Voorhis, Wesley C; Ortega-Mora, Luis Miguel (2019). Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy. Antimicrobial agents and chemotherapy, 63(7) American Society for Microbiology 10.1128/AAC.02527-18

[img] Text
Sanchez-Sanchez_2019_AAC.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (2MB) | Request a copy

Previous studies on drug efficacy showed low protection against abortion and vertical transmission of Toxoplasma gondii in pregnant sheep. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. Here, we present the safety and efficacy of BKI-1294 treatment (dosed orally at 100 mg/kg of body weight 5 times every 48 h) initiated 48 h after oral infection of sheep at midpregnancy with 1,000 TgShSp1 oocysts. BKI-1294 demonstrated systemic exposure in pregnant ewes, with maximum plasma concentrations of 2 to 3 μM and trough concentrations of 0.4 μM at 48 h after each dose. Oral administration of BKI-1294 in uninfected sheep at midpregnancy was deemed safe, since there were no changes in behavior, fecal consistency, rectal temperatures, hematological and biochemical parameters, or fetal mortality/morbidity. In ewes infected with a T. gondii oocyst dose lethal for fetuses, BKI-1294 treatment led to a minor rectal temperature increase after infection and a decrease in fetal/lamb mortality of 71%. None of the lambs born alive in the treated group exhibited congenital encephalitis lesions, and vertical transmission was prevented in 53% of them. BKI-1294 treatment during infection led to strong interferon gamma production after cell stimulation in vitro and a low humoral immune response to soluble tachyzoite antigens but high levels of anti-SAG1 antibodies. The results demonstrate a proof of concept for the therapeutic use of BKI-1294 to protect ovine fetuses from T. gondii infection during pregnancy.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Hemphill, Andrew

Subjects:

600 Technology > 630 Agriculture

ISSN:

0066-4804

Publisher:

American Society for Microbiology

Language:

English

Submitter:

Andrew Hemphill

Date Deposited:

17 Feb 2021 14:57

Last Modified:

17 Feb 2021 14:57

Publisher DOI:

10.1128/AAC.02527-18

PubMed ID:

31061151

Uncontrolled Keywords:

BKI-1294 Toxoplasma gondii abortion protein kinase inhibitor safety sheep treatment vertical transmission

BORIS DOI:

10.48350/152380

URI:

https://boris.unibe.ch/id/eprint/152380

Actions (login required)

Edit item Edit item
Provide Feedback