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Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma

Aminoglycoside antibiotics target the ribosomal decoding A-site and are active against a broad spectrum of bacteria. These compounds bind to a highly conserved stem-loop-stem structure in helix 44 of bacterial 16S rRNA. One particular aminoglycoside, paromomycin, also shows potent antiprotozoal acti...

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Autores principales: Hobbie, Sven N., Kaiser, Marcel, Schmidt, Sebastian, Shcherbakov, Dmitri, Janusic, Tanja, Brun, Reto, Böttger, Erik C.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101183/
https://www.ncbi.nlm.nih.gov/pubmed/21629725
http://dx.doi.org/10.1371/journal.pntd.0001161
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author Hobbie, Sven N.
Kaiser, Marcel
Schmidt, Sebastian
Shcherbakov, Dmitri
Janusic, Tanja
Brun, Reto
Böttger, Erik C.
author_facet Hobbie, Sven N.
Kaiser, Marcel
Schmidt, Sebastian
Shcherbakov, Dmitri
Janusic, Tanja
Brun, Reto
Böttger, Erik C.
author_sort Hobbie, Sven N.
collection PubMed
description Aminoglycoside antibiotics target the ribosomal decoding A-site and are active against a broad spectrum of bacteria. These compounds bind to a highly conserved stem-loop-stem structure in helix 44 of bacterial 16S rRNA. One particular aminoglycoside, paromomycin, also shows potent antiprotozoal activity and is used for the treatment of parasitic infections, e.g. by Leishmania spp. The precise drug target is, however, unclear; in particular whether aminoglycoside antibiotics target the cytosolic and/or the mitochondrial protozoan ribosome. To establish an experimental model for the study of protozoan decoding-site function, we constructed bacterial chimeric ribosomes where the central part of bacterial 16S rRNA helix 44 has been replaced by the corresponding Leishmania and Trypanosoma rRNA sequences. Relating the results from in-vitro ribosomal assays to that of in-vivo aminoglycoside activity against Trypanosoma brucei, as assessed in cell cultures and in a mouse model of infection, we conclude that aminoglycosides affect cytosolic translation while the mitochondrial ribosome of trypanosomes is not a target for aminoglycoside antibiotics.
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spelling pubmed-31011832011-05-31 Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma Hobbie, Sven N. Kaiser, Marcel Schmidt, Sebastian Shcherbakov, Dmitri Janusic, Tanja Brun, Reto Böttger, Erik C. PLoS Negl Trop Dis Research Article Aminoglycoside antibiotics target the ribosomal decoding A-site and are active against a broad spectrum of bacteria. These compounds bind to a highly conserved stem-loop-stem structure in helix 44 of bacterial 16S rRNA. One particular aminoglycoside, paromomycin, also shows potent antiprotozoal activity and is used for the treatment of parasitic infections, e.g. by Leishmania spp. The precise drug target is, however, unclear; in particular whether aminoglycoside antibiotics target the cytosolic and/or the mitochondrial protozoan ribosome. To establish an experimental model for the study of protozoan decoding-site function, we constructed bacterial chimeric ribosomes where the central part of bacterial 16S rRNA helix 44 has been replaced by the corresponding Leishmania and Trypanosoma rRNA sequences. Relating the results from in-vitro ribosomal assays to that of in-vivo aminoglycoside activity against Trypanosoma brucei, as assessed in cell cultures and in a mouse model of infection, we conclude that aminoglycosides affect cytosolic translation while the mitochondrial ribosome of trypanosomes is not a target for aminoglycoside antibiotics. Public Library of Science 2011-05-24 /pmc/articles/PMC3101183/ /pubmed/21629725 http://dx.doi.org/10.1371/journal.pntd.0001161 Text en Hobbie et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Hobbie, Sven N.
Kaiser, Marcel
Schmidt, Sebastian
Shcherbakov, Dmitri
Janusic, Tanja
Brun, Reto
Böttger, Erik C.
Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma
title Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma
title_full Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma
title_fullStr Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma
title_full_unstemmed Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma
title_short Genetic Reconstruction of Protozoan rRNA Decoding Sites Provides a Rationale for Paromomycin Activity against Leishmania and Trypanosoma
title_sort genetic reconstruction of protozoan rrna decoding sites provides a rationale for paromomycin activity against leishmania and trypanosoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101183/
https://www.ncbi.nlm.nih.gov/pubmed/21629725
http://dx.doi.org/10.1371/journal.pntd.0001161
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