Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii In Vitro and in Pregnant Mice Infected with T. gondii Oocysts

Ramseier, Jessica; Imhof, Dennis; Anghel, Nicoleta; Hänggeli, Kai; Beteck, Richard M.; Balmer, Vreni; Ortega-Mora, Luis-Miguel; Sanchez-Sanchez, Roberto; Ferre, Ignacio; Haynes, Richard K.; Hemphill, Andrew (2021). Assessment of the Activity of Decoquinate and Its Quinoline-O-Carbamate Derivatives against Toxoplasma gondii In Vitro and in Pregnant Mice Infected with T. gondii Oocysts. Molecules, 26(21), p. 6393. Molecular Diversity Preservation International MDPI 10.3390/molecules26216393

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Abstract: 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Ramseier, Jessica; Imhof, Dennis; Anghel, Nicoleta; Hänggeli, Kai Pascal Alexander; Balmer, Vreni and Hemphill, Andrew

Subjects:

600 Technology > 630 Agriculture

ISSN:

1420-3049

Publisher:

Molecular Diversity Preservation International MDPI

Language:

English

Submitter:

Katharina Gerber-Paizs

Date Deposited:

10 Nov 2021 10:59

Last Modified:

10 Nov 2021 10:59

Publisher DOI:

10.3390/molecules26216393

BORIS DOI:

10.48350/160680

URI:

https://boris.unibe.ch/id/eprint/160680

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