title: Bumped kinase inhibitor prohibits egression in Babesia bovis.
abstract: 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 Babesia 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.
authors.affiliation: Department of Veterinary Microbiology & Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Pedroni
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA, USA.
authors.forename: Rama Subba Rao
authors.initials: RS
authors.lastname: Vidadala
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center of Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Choi
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center of Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA, USA; Department of Pharmacy, University of Washington, Seattle, WA, USA.
authors.forename: Katelyn R
authors.initials: KR
authors.lastname: Keyloun
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center of Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA, USA.
authors.forename: Molly C
authors.initials: MC
authors.lastname: Reid
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center of Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA, USA.
authors.forename: Lynn K
authors.initials: LK
authors.lastname: Barrett
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center of Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA, USA.
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA, USA; Department of Biochemistry, University of Washington, Seattle, WA, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.affiliation: Department of Medicine, Division of Allergy and Infectious Diseases, Center of Emerging and Re-emerging Infectious Diseases (CERID), University of Washington, Seattle, WA, USA. Electronic address: ojo67kk@u.washington.edu.
authors.forename: Kayode K
authors.initials: KK
authors.lastname: Ojo
authors.affiliation: Department of Veterinary Microbiology & Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA, USA. Electronic address: laua@vetmed.wsu.edu.
authors.forename: Audrey O T
authors.initials: AO
authors.lastname: Lau
mesh_terms: D000818:Animals; D016793:Babesia bovis / Q000187:drug effects*; D002478:Cells, Cultured; D004912:Erythrocytes / Q000469:parasitology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors
keywords: Babesia; Bumped kinase inhibitors; Chemotherapy; Egression; Static