{"doi":"10.1128/aac.01448-24","title":"Treatment with BKI-1748 after <i>Toxoplasma gondii</i> systemic dissemination in experimentally infected pregnant sheep improves fetal and lamb mortality and morbidity and prevents congenital infection","abstract":"ABSTRACT Drug development for congenital toxoplasmosis is challenging since first-line therapy has a high rate of adverse effects and exhibits suboptimal efficacy. Bumped kinase inhibitors (BKIs), targeting protein kinases with small gatekeeper residues, have been found to be effective against Toxoplasma gondii . The efficacy of BKI-1748 administered later than 2 days post-infection (p.i.), a scenario that may better reflect its real-world use as a therapeutic candidate, has not been investigated in T. gondii -infected pregnant sheep. For this purpose, 19 pregnant sheep were assigned to three experimental groups. Group 1 (G1, n = 8) and group 2 (G2, n = 8) were dosed orally with 10 TgShSp1 sporulated oocysts at 90 days of gestation (dg). Animals from group 3 (G3, n = 3) were simultaneously mock dosed with phosphate-buffered solution (PBS). In G1, BKI-1748 was administered orally from day 7 p.i. (fever and increased serum IFNγ levels) onward, maintaining drug exposure for 20 days (10 doses at 15 mg/kg every 2 days). Treated animals (G1) exhibited significantly lower rectal temperatures (on days 8 and 9 p.i.), serum IFNγ levels (on day 10 p.i.), and specific IgG levels when compared with non-treated animals (G2). At delivery, significantly higher percentages of healthy lambs were found in infected/treated sheep in G1 (73.3%) and in uninfected sheep in G3 (80%) compared with infected/untreated sheep in G2 (31.3%). Concerning congenital transmission, parasite DNA was neither detected in placenta nor target tissues (brain and lungs) from the fetuses/lambs in G1(infected/treated) and G3 (uninfected). By contrast, parasite DNA was detected in all placentas and lambs from G2 (infected/untreated), except for one sheep that aborted on day 13 p.i.","journal":"Antimicrobial Agents and Chemotherapy","year":2024,"id":446239,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1263074,"name":"Ana Huertas-López","orcid":"0000-0002-9627-7658","position":1,"is_corresponding":false},{"id":1263075,"name":"Andrea Largo-de la Torre","orcid":"0000-0003-3432-3388","position":2,"is_corresponding":false},{"id":484784,"name":"Ignacio Ferre","orcid":"0000-0001-5402-6626","position":3,"is_corresponding":false},{"id":1263076,"name":"Filippo Maria Dini","orcid":"0000-0001-7378-8650","position":4,"is_corresponding":false},{"id":765857,"name":"Michela Re","orcid":"0000-0002-9494-9940","position":5,"is_corresponding":false},{"id":1109134,"name":"Javier Moreno-Gonzalo","orcid":"0000-0002-5282-0428","position":6,"is_corresponding":false},{"id":352971,"name":"Ryan Choi","orcid":"0000-0001-9374-5893","position":7,"is_corresponding":false},{"id":352972,"name":"Matthew A. Hulverson","orcid":"0000-0002-3413-4969","position":8,"is_corresponding":false},{"id":352988,"name":"Kayode K. Ojo","orcid":"0000-0002-2007-2170","position":9,"is_corresponding":false},{"id":352982,"name":"Samuel L.M. Arnold","orcid":"0000-0001-8290-2347","position":10,"is_corresponding":false},{"id":352979,"name":"Andrew Hemphill","orcid":"0000-0002-0622-2128","position":11,"is_corresponding":false},{"id":352989,"name":"Wesley C. Van Voorhis","orcid":"0000-0001-6141-2015","position":12,"is_corresponding":false},{"id":352980,"name":"Luis Miguel Ortega‐Mora","orcid":"0000-0002-4986-6783","position":13,"is_corresponding":false},{"id":484785,"name":"Roberto Sánchez-Sánchez","orcid":"0000-0002-5067-2636","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T02:01:50.465308Z","pmid":"39745365","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}