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

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 fibro...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	quinolone decoquinate <i>Toxoplasma gondii</i> tachyzoites bradyzoites oocysts Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/a86f5c8d037a44fca41c7ec06a97d3ad
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spelling	oai:doaj.org-article:a86f5c8d037a44fca41c7ec06a97d3ad2021-11-11T18:25:03ZAssessment 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> Oocysts10.3390/molecules262163931420-3049https://doaj.org/article/a86f5c8d037a44fca41c7ec06a97d3ad2021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6393https://doaj.org/toc/1420-3049The 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 <i>Toxoplasma gondii</i> 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 (IC<sub>50</sub>) of 1.1 nM and the high selectivity index of >5000, the efficacy of oral treatment of pregnant mice experimentally infected with <i>T. gondii</i> oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than <i>T. gondii</i> infection alone, and did not prevent vertical transmission. Thus, three quinoline-<i>O</i>-carbamate derivatives of DCQ, anticipated to have better physicochemical properties than DCQ, were assessed in vitro. One such compound, RMB060, displayed an exceedingly low IC<sub>50</sub> 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 <i>T. gondii</i> oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.Jessica RamseierDennis ImhofNicoleta AnghelKai HänggeliRichard M. BeteckVreni BalmerLuis-Miguel Ortega-MoraRoberto Sanchez-SanchezIgnacio FerreRichard K. HaynesAndrew HemphillMDPI AGarticlequinolonedecoquinate<i>Toxoplasma gondii</i>tachyzoitesbradyzoitesoocystsOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6393, p 6393 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	quinolone decoquinate <i>Toxoplasma gondii</i> tachyzoites bradyzoites oocysts Organic chemistry QD241-441
spellingShingle	quinolone decoquinate <i>Toxoplasma gondii</i> tachyzoites bradyzoites oocysts Organic chemistry QD241-441 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 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
description	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 <i>Toxoplasma gondii</i> 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 (IC<sub>50</sub>) of 1.1 nM and the high selectivity index of >5000, the efficacy of oral treatment of pregnant mice experimentally infected with <i>T. gondii</i> oocysts with DCQ at 10 mg/kg/day for 5 days was assessed. However, the treatment had detrimental effects, induced higher neonatal mortality than <i>T. gondii</i> infection alone, and did not prevent vertical transmission. Thus, three quinoline-<i>O</i>-carbamate derivatives of DCQ, anticipated to have better physicochemical properties than DCQ, were assessed in vitro. One such compound, RMB060, displayed an exceedingly low IC<sub>50</sub> 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 <i>T. gondii</i> oocysts with RMB060 did reduce parasite burden in non-pregnant mice and dams, but vertical transmission to pups could not be prevented.
format	article
author	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
author_facet	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
author_sort	Jessica Ramseier
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a86f5c8d037a44fca41c7ec06a97d3ad
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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

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