Abstract
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.
Highlights
Calcium-dependent protein kinases (CDPKs) are promising targets for the development of anti-apicomplexan drugs (Hui et al, 2015; Kugelstadt et al, 2011; Ojo et al, 2013)
The role of CDPKs and their potential as molecular targets for chemotherapeutic intervention in apicomplexan parasites has previously been studied in parasites of different taxonomic groups
Cystoisospora suis CDPK1 (CsCDPK1) auto-phosphorylation activity could be measured in the presence or absence of calcium and with or without a suitable peptide substrate
Summary
Calcium-dependent protein kinases (CDPKs) are promising targets for the development of anti-apicomplexan drugs (Hui et al, 2015; Kugelstadt et al, 2011; Ojo et al, 2013). Apicomplexan CDPKs, belonging to a superfamily of serine-threonine kinases, are among the most abundant classes of calcium sensors and are crucial for multiple physiological functions such as gliding, cell invasion, egress and replication (Kugelstadt et al, 2011; Ojo et al, 2012). Most importantly, these CDPKs are absent in mammalian hosts, rendering them excellent parasite-specific drug targets (Billker et al, 2009; Larson et al, 2012; Ojo et al, 2010). This allows for BKIs with large aromatic moieties displayed from
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More From: International Journal for Parasitology: Drugs and Drug Resistance
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