Endochin-like quinolones (ELQs) and bumped kinase inhibitors (BKIs): Synergistic and additive effects of combined treatments against Neospora caninum infection in vitro and in vivo. (December 2021)

• Record Type: Journal Article
• Authors: Anghel, Nicoleta; Imhof, Dennis; Winzer, Pablo; Balmer, Vreni; Ramseier, Jessica; Haenggeli, Kai; Choi, Ryan; Hulverson, Matthew A.; Whitman, Grant R.; Arnold, Samuel L.M.; Ojo, Kayode K.; Van Voorhis, Wesley C.; Doggett, J. Stone; Ortega-Mora, Luis M.; Hemphill, Andrew
• Is Part Of: International journal for parasitology. Volume 17(2021)
• Page Start: 92
• Page End: 106
• Publication Date: 2021-12
• Subjects: Endochin-like quinolones -- Bumped kinase inhibitors -- Cytochrome bc1 -- Calcium-dependent protein kinase inhibitor -- Neosporosis -- Tachyzoites -- Antiparasitic therapy -- Combination therapy; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2021.08.007
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: The apicomplexan parasite Neospora caninum is an important causative agent of congenital neosporosis, resulting in abortion, birth of weak offspring and neuromuscular disorders in cattle, sheep, and many other species. Among several compound classes that are currently being developed, two have been reported to limit the effects of congenital neosporosis: (i) bumped kinase inhibitors (BKIs) target calcium dependent protein kinase 1 (CDPK1), an enzyme that is encoded by an apicoplast-derived gene and found only in apicomplexans and plants. CDPK1 is essential for host cell invasion and egress; (ii) endochin-like quinolones (ELQs) are inhibitors of the cytochrome bc 1 complex of the mitochondrial electron transport chain and thus inhibit oxidative phosphorylation. We here report on the in vitro and in vivo activities of BKI-1748, and of ELQ-316 and its respective prodrugs ELQ-334 and ELQ-422, applied either as single-compounds or ELQ-BKI-combinations. In vitro, BKI-1748 and ELQ-316, as well as BKI-1748 and ELQ-334, acted synergistically, while this was not observed for the BKI-1748/ELQ-422 combination treatment. In a N. caninum -infected pregnant BALB/c mouse model, the synergistic effects observed in vitro were not entirely reproduced, but 100% postnatal survival and 100% inhibition of vertical transmission was noted in the group treated with the BKI-1748/ELQ-334 combination. In addition, the combined drug applications resulted in lower neonatal mortality compared to treatments with single drugs. Graphical abstract: Image 1 Highlights: BKI-1748 is a bumped kinase inhibitor with anti-Neospora activity in vitro and in vivo Endochin-like quinolones target the cytochrome bc 1 complex and exhibit anti-Neospora properties. Single and combined applications of these two compound classes do not interfere in pregnancy outcome in mice BKI-1748/ELQ-334 combination treatment results in 100% postnatal survival and blocks vertical transmission in the neosporosis mouse model