Cell Cycle Inhibition To Treat Sleeping Sickness

ABSTRACT African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle in...

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Autores principales:	Conrad L. Epting, Brian T. Emmer, Nga Y. Du, Joann M. Taylor, Ming Y. Makanji, Cheryl L. Olson, David M. Engman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	African sleeping sickness Trypanosoma brucei hydroxyurea ribonucleotide reductase Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/31d7a561c496421a96c0f83003ea87a1
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spelling	oai:doaj.org-article:31d7a561c496421a96c0f83003ea87a12021-11-15T15:51:50ZCell Cycle Inhibition To Treat Sleeping Sickness10.1128/mBio.01427-172150-7511https://doaj.org/article/31d7a561c496421a96c0f83003ea87a12017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01427-17https://doaj.org/toc/2150-7511ABSTRACT African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR), which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo. These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens. IMPORTANCE The development of drugs to treat infections with eukaryotic pathogens is challenging because many key virulence factors have closely related homologues in humans. Drug toxicity greatly limits these development efforts. For pathogens that replicate at a high rate, especially in the blood, an alternative approach is to target the cell cycle directly, much as is done to treat some hematologic malignancies. The results presented here indicate that targeting the cell cycle via inhibition of ribonucleotide reductase is effective at killing trypanosomes and prolonging the survival of infected animals.Conrad L. EptingBrian T. EmmerNga Y. DuJoann M. TaylorMing Y. MakanjiCheryl L. OlsonDavid M. EngmanAmerican Society for MicrobiologyarticleAfrican sleeping sicknessTrypanosoma bruceihydroxyurearibonucleotide reductaseMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	African sleeping sickness Trypanosoma brucei hydroxyurea ribonucleotide reductase Microbiology QR1-502
spellingShingle	African sleeping sickness Trypanosoma brucei hydroxyurea ribonucleotide reductase Microbiology QR1-502 Conrad L. Epting Brian T. Emmer Nga Y. Du Joann M. Taylor Ming Y. Makanji Cheryl L. Olson David M. Engman Cell Cycle Inhibition To Treat Sleeping Sickness
description	ABSTRACT African trypanosomiasis is caused by infection with the protozoan parasite Trypanosoma brucei. During infection, this pathogen divides rapidly to high density in the bloodstream of its mammalian host in a manner similar to that of leukemia. Like all eukaryotes, T. brucei has a cell cycle involving the de novo synthesis of DNA regulated by ribonucleotide reductase (RNR), which catalyzes the conversion of ribonucleotides into their deoxy form. As an essential enzyme for the cell cycle, RNR is a common target for cancer chemotherapy. We hypothesized that inhibition of RNR by genetic or pharmacological means would impair parasite growth in vitro and prolong the survival of infected animals. Our results demonstrate that RNR inhibition is highly effective in suppressing parasite growth both in vitro and in vivo. These results support drug discovery efforts targeting the cell cycle, not only for African trypanosomiasis but possibly also for other infections by eukaryotic pathogens. IMPORTANCE The development of drugs to treat infections with eukaryotic pathogens is challenging because many key virulence factors have closely related homologues in humans. Drug toxicity greatly limits these development efforts. For pathogens that replicate at a high rate, especially in the blood, an alternative approach is to target the cell cycle directly, much as is done to treat some hematologic malignancies. The results presented here indicate that targeting the cell cycle via inhibition of ribonucleotide reductase is effective at killing trypanosomes and prolonging the survival of infected animals.
format	article
author	Conrad L. Epting Brian T. Emmer Nga Y. Du Joann M. Taylor Ming Y. Makanji Cheryl L. Olson David M. Engman
author_facet	Conrad L. Epting Brian T. Emmer Nga Y. Du Joann M. Taylor Ming Y. Makanji Cheryl L. Olson David M. Engman
author_sort	Conrad L. Epting
title	Cell Cycle Inhibition To Treat Sleeping Sickness
title_short	Cell Cycle Inhibition To Treat Sleeping Sickness
title_full	Cell Cycle Inhibition To Treat Sleeping Sickness
title_fullStr	Cell Cycle Inhibition To Treat Sleeping Sickness
title_full_unstemmed	Cell Cycle Inhibition To Treat Sleeping Sickness
title_sort	cell cycle inhibition to treat sleeping sickness
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/31d7a561c496421a96c0f83003ea87a1
work_keys_str_mv	AT conradlepting cellcycleinhibitiontotreatsleepingsickness AT briantemmer cellcycleinhibitiontotreatsleepingsickness AT ngaydu cellcycleinhibitiontotreatsleepingsickness AT joannmtaylor cellcycleinhibitiontotreatsleepingsickness AT mingymakanji cellcycleinhibitiontotreatsleepingsickness AT cheryllolson cellcycleinhibitiontotreatsleepingsickness AT davidmengman cellcycleinhibitiontotreatsleepingsickness
_version_	1718427326913445888

Cell Cycle Inhibition To Treat Sleeping Sickness

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