Assessment of the Activity of Decoquinate and Its Quinoline-<i>O</i>-Carbamate Derivatives against <i>Toxoplasma gondii</i> In Vitro and in Pregnant Mice Infected with <i>T. gondii</i> Oocysts
Jessica Ramseier,
Dennis Imhof,
Nicoleta Anghel,
Kai Hänggeli,
Richard M. Beteck,
Vreni Balmer,
Luis-Miguel Ortega-Mora,
Roberto Sanchez-Sanchez,
Ignacio Ferre,
Richard K. Haynes,
Andrew Hemphill
Affiliations
Jessica Ramseier
Institute of Parasitology, Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland
Dennis Imhof
Institute of Parasitology, Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland
Nicoleta Anghel
Institute of Parasitology, Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland
Kai Hänggeli
Institute of Parasitology, Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland
Richard M. Beteck
Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom 2520, South Africa
Vreni Balmer
Institute of Parasitology, Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland
Luis-Miguel Ortega-Mora
SALUVET, Animal Health Department, Faculty of Veterinary Sciences, Complutense University of Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain
Roberto Sanchez-Sanchez
SALUVET, Animal Health Department, Faculty of Veterinary Sciences, Complutense University of Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain
Ignacio Ferre
SALUVET, Animal Health Department, Faculty of Veterinary Sciences, Complutense University of Madrid, Ciudad Universitaria s/n, 28040 Madrid, Spain
Richard K. Haynes
Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom 2520, South Africa
Andrew Hemphill
Institute of Parasitology, Vetsuisse Faculty, Department of Infectious Diseases and Pathobiology, University of Bern, Länggass-Strasse 122, 3012 Bern, Switzerland
The quinolone decoquinate (DCQ) is widely used in veterinary practice for the treatment of bacterial and parasitic infections, most notably, coccidiosis in poultry and in ruminants. We have investigated the effects of treatment of Toxoplasma gondii in infected human foreskin fibroblasts (HFF) with DCQ. This induced distinct alterations in the parasite mitochondrion within 24 h, which persisted even after long-term (500 nM, 52 days) treatment, although there was no parasiticidal effect. Based on the low half-maximal effective concentration (IC50) of 1.1 nM and the high selectivity index of >5000, the efficacy of oral treatment of pregnant mice experimentally infected with T. gondii oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than T. gondii infection alone, and did not prevent vertical transmission. Thus, three quinoline-O-carbamate derivatives of DCQ, anticipated to have better physicochemical properties than DCQ, were assessed in vitro. One such compound, RMB060, displayed an exceedingly low IC50 of 0.07 nM, when applied concomitantly with the infection of host cells and had no impact on HFF viability at 10 µM. As was the case for DCQ, RMB060 treatment resulted in the alteration of the mitochondrial matrix and loss of cristae, but the changes became apparent at just 6 h after the commencement of treatment. After 48 h, RMB060 induced the expression of the bradyzoite antigen BAG1, but TEM did not reveal any other features reminiscent of bradyzoites. The exposure of infected cultures to 300 nM RMB060 for 52 days did not result in the complete killing of all tachyzoites, although mitochondria remained ultrastructurally damaged and there was a slower proliferation rate. The treatment of mice infected with T. gondii oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.
