Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target

Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Magee...
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Autor*in:	Vanessa M. Howieson [verfasserIn] Joy Zeng [verfasserIn] Joachim Kloehn [verfasserIn] Christina Spry [verfasserIn] Chiara Marchetti [verfasserIn] Matteo Lunghi [verfasserIn] Emmanuel Varesio [verfasserIn] Andrew Soper [verfasserIn] Anthony G. Coyne [verfasserIn] Chris Abell [verfasserIn] Giel G. van Dooren [verfasserIn] Kevin J. Saliba [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Pantothenate synthetase Pantoate β-alanine ligase T. gondii SW314 Pantothenate PanC

Übergeordnetes Werk:	In: International Journal for Parasitology: Drugs and Drug Resistance - Elsevier, 2015, 22(2023), Seite 8
Übergeordnetes Werk:	volume:22 ; year:2023 ; pages:8

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.ijpddr.2023.03.003

Katalog-ID:	DOAJ088826074

Internformat


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245	1	0	\|a Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target
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520			\|a Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites.
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700	0		\|a Giel G. van Dooren \|e verfasserin \|4 aut
700	0		\|a Kevin J. Saliba \|e verfasserin \|4 aut
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912			\|a GBV_ILN_151
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912			\|a GBV_ILN_206
912			\|a GBV_ILN_213
912			\|a GBV_ILN_224
912			\|a GBV_ILN_230
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_602
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912			\|a GBV_ILN_2055
912			\|a GBV_ILN_2056
912			\|a GBV_ILN_2059
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912			\|a GBV_ILN_2106
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912			\|a GBV_ILN_2122
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912			\|a GBV_ILN_2232
912			\|a GBV_ILN_2336
912			\|a GBV_ILN_2470
912			\|a GBV_ILN_2507
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4035
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allfields	10.1016/j.ijpddr.2023.03.003 doi (DE-627)DOAJ088826074 (DE-599)DOAJ00b024bbf99f4341a185721a0ef4505e DE-627 ger DE-627 rakwb eng RC109-216 Vanessa M. Howieson verfasserin aut Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites. Pantothenate synthetase Pantoate β-alanine ligase T. gondii SW314 Pantothenate PanC Infectious and parasitic diseases Joy Zeng verfasserin aut Joachim Kloehn verfasserin aut Christina Spry verfasserin aut Chiara Marchetti verfasserin aut Matteo Lunghi verfasserin aut Emmanuel Varesio verfasserin aut Andrew Soper verfasserin aut Anthony G. Coyne verfasserin aut Chris Abell verfasserin aut Giel G. van Dooren verfasserin aut Kevin J. Saliba verfasserin aut In International Journal for Parasitology: Drugs and Drug Resistance Elsevier, 2015 22(2023), Seite 8 (DE-627)776855328 (DE-600)2751132-7 22113207 nnns volume:22 year:2023 pages:8 https://doi.org/10.1016/j.ijpddr.2023.03.003 kostenfrei https://doaj.org/article/00b024bbf99f4341a185721a0ef4505e kostenfrei http://www.sciencedirect.com/science/article/pii/S2211320723000118 kostenfrei https://doaj.org/toc/2211-3207 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 22 2023 8
spelling	10.1016/j.ijpddr.2023.03.003 doi (DE-627)DOAJ088826074 (DE-599)DOAJ00b024bbf99f4341a185721a0ef4505e DE-627 ger DE-627 rakwb eng RC109-216 Vanessa M. Howieson verfasserin aut Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites. Pantothenate synthetase Pantoate β-alanine ligase T. gondii SW314 Pantothenate PanC Infectious and parasitic diseases Joy Zeng verfasserin aut Joachim Kloehn verfasserin aut Christina Spry verfasserin aut Chiara Marchetti verfasserin aut Matteo Lunghi verfasserin aut Emmanuel Varesio verfasserin aut Andrew Soper verfasserin aut Anthony G. Coyne verfasserin aut Chris Abell verfasserin aut Giel G. van Dooren verfasserin aut Kevin J. Saliba verfasserin aut In International Journal for Parasitology: Drugs and Drug Resistance Elsevier, 2015 22(2023), Seite 8 (DE-627)776855328 (DE-600)2751132-7 22113207 nnns volume:22 year:2023 pages:8 https://doi.org/10.1016/j.ijpddr.2023.03.003 kostenfrei https://doaj.org/article/00b024bbf99f4341a185721a0ef4505e kostenfrei http://www.sciencedirect.com/science/article/pii/S2211320723000118 kostenfrei https://doaj.org/toc/2211-3207 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 22 2023 8
allfields_unstemmed	10.1016/j.ijpddr.2023.03.003 doi (DE-627)DOAJ088826074 (DE-599)DOAJ00b024bbf99f4341a185721a0ef4505e DE-627 ger DE-627 rakwb eng RC109-216 Vanessa M. Howieson verfasserin aut Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites. Pantothenate synthetase Pantoate β-alanine ligase T. gondii SW314 Pantothenate PanC Infectious and parasitic diseases Joy Zeng verfasserin aut Joachim Kloehn verfasserin aut Christina Spry verfasserin aut Chiara Marchetti verfasserin aut Matteo Lunghi verfasserin aut Emmanuel Varesio verfasserin aut Andrew Soper verfasserin aut Anthony G. Coyne verfasserin aut Chris Abell verfasserin aut Giel G. van Dooren verfasserin aut Kevin J. Saliba verfasserin aut In International Journal for Parasitology: Drugs and Drug Resistance Elsevier, 2015 22(2023), Seite 8 (DE-627)776855328 (DE-600)2751132-7 22113207 nnns volume:22 year:2023 pages:8 https://doi.org/10.1016/j.ijpddr.2023.03.003 kostenfrei https://doaj.org/article/00b024bbf99f4341a185721a0ef4505e kostenfrei http://www.sciencedirect.com/science/article/pii/S2211320723000118 kostenfrei https://doaj.org/toc/2211-3207 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 22 2023 8
allfieldsGer	10.1016/j.ijpddr.2023.03.003 doi (DE-627)DOAJ088826074 (DE-599)DOAJ00b024bbf99f4341a185721a0ef4505e DE-627 ger DE-627 rakwb eng RC109-216 Vanessa M. Howieson verfasserin aut Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites. Pantothenate synthetase Pantoate β-alanine ligase T. gondii SW314 Pantothenate PanC Infectious and parasitic diseases Joy Zeng verfasserin aut Joachim Kloehn verfasserin aut Christina Spry verfasserin aut Chiara Marchetti verfasserin aut Matteo Lunghi verfasserin aut Emmanuel Varesio verfasserin aut Andrew Soper verfasserin aut Anthony G. Coyne verfasserin aut Chris Abell verfasserin aut Giel G. van Dooren verfasserin aut Kevin J. Saliba verfasserin aut In International Journal for Parasitology: Drugs and Drug Resistance Elsevier, 2015 22(2023), Seite 8 (DE-627)776855328 (DE-600)2751132-7 22113207 nnns volume:22 year:2023 pages:8 https://doi.org/10.1016/j.ijpddr.2023.03.003 kostenfrei https://doaj.org/article/00b024bbf99f4341a185721a0ef4505e kostenfrei http://www.sciencedirect.com/science/article/pii/S2211320723000118 kostenfrei https://doaj.org/toc/2211-3207 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 22 2023 8
allfieldsSound	10.1016/j.ijpddr.2023.03.003 doi (DE-627)DOAJ088826074 (DE-599)DOAJ00b024bbf99f4341a185721a0ef4505e DE-627 ger DE-627 rakwb eng RC109-216 Vanessa M. Howieson verfasserin aut Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites. Pantothenate synthetase Pantoate β-alanine ligase T. gondii SW314 Pantothenate PanC Infectious and parasitic diseases Joy Zeng verfasserin aut Joachim Kloehn verfasserin aut Christina Spry verfasserin aut Chiara Marchetti verfasserin aut Matteo Lunghi verfasserin aut Emmanuel Varesio verfasserin aut Andrew Soper verfasserin aut Anthony G. Coyne verfasserin aut Chris Abell verfasserin aut Giel G. van Dooren verfasserin aut Kevin J. Saliba verfasserin aut In International Journal for Parasitology: Drugs and Drug Resistance Elsevier, 2015 22(2023), Seite 8 (DE-627)776855328 (DE-600)2751132-7 22113207 nnns volume:22 year:2023 pages:8 https://doi.org/10.1016/j.ijpddr.2023.03.003 kostenfrei https://doaj.org/article/00b024bbf99f4341a185721a0ef4505e kostenfrei http://www.sciencedirect.com/science/article/pii/S2211320723000118 kostenfrei https://doaj.org/toc/2211-3207 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 22 2023 8
language	English
source	In International Journal for Parasitology: Drugs and Drug Resistance 22(2023), Seite 8 volume:22 year:2023 pages:8
sourceStr	In International Journal for Parasitology: Drugs and Drug Resistance 22(2023), Seite 8 volume:22 year:2023 pages:8
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Pantothenate synthetase Pantoate β-alanine ligase T. gondii SW314 Pantothenate PanC Infectious and parasitic diseases
isfreeaccess_bool	true
container_title	International Journal for Parasitology: Drugs and Drug Resistance
authorswithroles_txt_mv	Vanessa M. Howieson @@aut@@ Joy Zeng @@aut@@ Joachim Kloehn @@aut@@ Christina Spry @@aut@@ Chiara Marchetti @@aut@@ Matteo Lunghi @@aut@@ Emmanuel Varesio @@aut@@ Andrew Soper @@aut@@ Anthony G. Coyne @@aut@@ Chris Abell @@aut@@ Giel G. van Dooren @@aut@@ Kevin J. Saliba @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
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id	DOAJ088826074
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ088826074</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230501183737.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230410s2023 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1016/j.ijpddr.2023.03.003</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ088826074</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ00b024bbf99f4341a185721a0ef4505e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC109-216</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Vanessa M. Howieson</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. 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callnumber-first	R - Medicine
author	Vanessa M. Howieson
spellingShingle	Vanessa M. Howieson misc RC109-216 misc Pantothenate synthetase misc Pantoate β-alanine ligase misc T. gondii misc SW314 misc Pantothenate misc PanC misc Infectious and parasitic diseases Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target
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topic_title	RC109-216 Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target Pantothenate synthetase Pantoate β-alanine ligase T. gondii SW314 Pantothenate PanC
topic	misc RC109-216 misc Pantothenate synthetase misc Pantoate β-alanine ligase misc T. gondii misc SW314 misc Pantothenate misc PanC misc Infectious and parasitic diseases
topic_unstemmed	misc RC109-216 misc Pantothenate synthetase misc Pantoate β-alanine ligase misc T. gondii misc SW314 misc Pantothenate misc PanC misc Infectious and parasitic diseases
topic_browse	misc RC109-216 misc Pantothenate synthetase misc Pantoate β-alanine ligase misc T. gondii misc SW314 misc Pantothenate misc PanC misc Infectious and parasitic diseases
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title	Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target
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title_full	Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target
author_sort	Vanessa M. Howieson
journal	International Journal for Parasitology: Drugs and Drug Resistance
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author_browse	Vanessa M. Howieson Joy Zeng Joachim Kloehn Christina Spry Chiara Marchetti Matteo Lunghi Emmanuel Varesio Andrew Soper Anthony G. Coyne Chris Abell Giel G. van Dooren Kevin J. Saliba
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author-letter	Vanessa M. Howieson
doi_str_mv	10.1016/j.ijpddr.2023.03.003
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title_sort	pantothenate biosynthesis in toxoplasma gondii tachyzoites is not a drug target
callnumber	RC109-216
title_auth	Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target
abstract	Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites.
abstractGer	Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites.
abstract_unstemmed	Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites.
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title_short	Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target
url	https://doi.org/10.1016/j.ijpddr.2023.03.003 https://doaj.org/article/00b024bbf99f4341a185721a0ef4505e http://www.sciencedirect.com/science/article/pii/S2211320723000118 https://doaj.org/toc/2211-3207
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author2	Joy Zeng Joachim Kloehn Christina Spry Chiara Marchetti Matteo Lunghi Emmanuel Varesio Andrew Soper Anthony G. Coyne Chris Abell Giel G. van Dooren Kevin J. Saliba
author2Str	Joy Zeng Joachim Kloehn Christina Spry Chiara Marchetti Matteo Lunghi Emmanuel Varesio Andrew Soper Anthony G. Coyne Chris Abell Giel G. van Dooren Kevin J. Saliba
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doi_str	10.1016/j.ijpddr.2023.03.003
callnumber-a	RC109-216
up_date	2024-07-03T19:43:34.382Z
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Howieson</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. 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Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target

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