A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines
Descripción del Articulo
We are very thankful to Marcos Milla for donating equipment that was used in this study and others. We particularly thank Andrey Konevega and his team for providing the tRNAs that were used in this study. Also, we would like to thank all lab members of the Mil?n and Quiliano groups for their help, s...
| Autores: | , , , |
|---|---|
| Formato: | artículo |
| Fecha de Publicación: | 2021 |
| Institución: | Consejo Nacional de Ciencia Tecnología e Innovación |
| Repositorio: | CONCYTEC-Institucional |
| Lenguaje: | inglés |
| OAI Identifier: | oai:repositorio.concytec.gob.pe:20.500.12390/2954 |
| Enlace del recurso: | https://hdl.handle.net/20.500.12390/2954 https://doi.org/10.3389/fmicb.2021.682682 |
| Nivel de acceso: | acceso abierto |
| Materia: | translation initiation antibiotic initiation factor ribosome tetracycline tigecycline https://purl.org/pe-repo/ocde/ford#3.01.02 |
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| dc.title.none.fl_str_mv |
A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines |
| title |
A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines |
| spellingShingle |
A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines Barrenechea V. translation initiation antibiotic initiation factor ribosome tetracycline tigecycline https://purl.org/pe-repo/ocde/ford#3.01.02 |
| title_short |
A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines |
| title_full |
A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines |
| title_fullStr |
A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines |
| title_full_unstemmed |
A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines |
| title_sort |
A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines |
| author |
Barrenechea V. |
| author_facet |
Barrenechea V. Vargas-Reyes M. Quiliano M. Milón P. |
| author_role |
author |
| author2 |
Vargas-Reyes M. Quiliano M. Milón P. |
| author2_role |
author author author |
| dc.contributor.author.fl_str_mv |
Barrenechea V. Vargas-Reyes M. Quiliano M. Milón P. |
| dc.subject.none.fl_str_mv |
translation initiation |
| topic |
translation initiation antibiotic initiation factor ribosome tetracycline tigecycline https://purl.org/pe-repo/ocde/ford#3.01.02 |
| dc.subject.es_PE.fl_str_mv |
antibiotic initiation factor ribosome tetracycline tigecycline |
| dc.subject.ocde.none.fl_str_mv |
https://purl.org/pe-repo/ocde/ford#3.01.02 |
| description |
We are very thankful to Marcos Milla for donating equipment that was used in this study and others. We particularly thank Andrey Konevega and his team for providing the tRNAs that were used in this study. Also, we would like to thank all lab members of the Mil?n and Quiliano groups for their help, support, and fantastic working atmosphere. Funding. This work was supported by grants from the Peruvian Fondo Nacional de Desarrollo Cient?fico, Tecnol?gico y de Innovaci?n Tecnol?gica (154-2017-FONDECYT) and (036-2019-FONDECYT-BM-INC.INV) to PM and (406-2019-FONDECYT) to MQ and the Inn?vate Per? program (297-InnovatePeru-2016) to PM. Funding for open access was provided by the Universidad Peruana de Ciencias Aplicadas (C-014-2020). |
| publishDate |
2021 |
| dc.date.accessioned.none.fl_str_mv |
2024-05-30T23:13:38Z |
| dc.date.available.none.fl_str_mv |
2024-05-30T23:13:38Z |
| dc.date.issued.fl_str_mv |
2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.uri.none.fl_str_mv |
https://hdl.handle.net/20.500.12390/2954 |
| dc.identifier.doi.none.fl_str_mv |
https://doi.org/10.3389/fmicb.2021.682682 |
| dc.identifier.scopus.none.fl_str_mv |
2-s2.0-85109589171 |
| url |
https://hdl.handle.net/20.500.12390/2954 https://doi.org/10.3389/fmicb.2021.682682 |
| identifier_str_mv |
2-s2.0-85109589171 |
| dc.language.iso.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.ispartof.none.fl_str_mv |
Frontiers in Microbiology |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| dc.rights.uri.none.fl_str_mv |
https://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.publisher.none.fl_str_mv |
Frontiers Media S.A. |
| publisher.none.fl_str_mv |
Frontiers Media S.A. |
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reponame:CONCYTEC-Institucional instname:Consejo Nacional de Ciencia Tecnología e Innovación instacron:CONCYTEC |
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Consejo Nacional de Ciencia Tecnología e Innovación |
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CONCYTEC |
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CONCYTEC |
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CONCYTEC-Institucional |
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CONCYTEC-Institucional |
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Repositorio Institucional CONCYTEC |
| repository.mail.fl_str_mv |
repositorio@concytec.gob.pe |
| _version_ |
1844882994242781184 |
| spelling |
Publicationrp08357600rp08358600rp08359600rp05844600Barrenechea V.Vargas-Reyes M.Quiliano M.Milón P.2024-05-30T23:13:38Z2024-05-30T23:13:38Z2021https://hdl.handle.net/20.500.12390/2954https://doi.org/10.3389/fmicb.2021.6826822-s2.0-85109589171We are very thankful to Marcos Milla for donating equipment that was used in this study and others. We particularly thank Andrey Konevega and his team for providing the tRNAs that were used in this study. Also, we would like to thank all lab members of the Mil?n and Quiliano groups for their help, support, and fantastic working atmosphere. Funding. This work was supported by grants from the Peruvian Fondo Nacional de Desarrollo Cient?fico, Tecnol?gico y de Innovaci?n Tecnol?gica (154-2017-FONDECYT) and (036-2019-FONDECYT-BM-INC.INV) to PM and (406-2019-FONDECYT) to MQ and the Inn?vate Per? program (297-InnovatePeru-2016) to PM. Funding for open access was provided by the Universidad Peruana de Ciencias Aplicadas (C-014-2020).Tetracycline has positively impacted human health as well as the farming and animal industries. Its extensive usage and versatility led to the spread of resistance mechanisms followed by the development of new variants of the antibiotic. Tetracyclines inhibit bacterial growth by impeding the binding of elongator tRNAs to the ribosome. However, a small number of reports indicated that Tetracyclines could also inhibit translation initiation, yet the molecular mechanism remained unknown. Here, we use biochemical and computational methods to study how Oxytetracycline (Otc), Demeclocycline (Dem), and Tigecycline (Tig) affect the translation initiation phase of protein synthesis. Our results show that all three Tetracyclines induce Initiation Factor IF3 to adopt a compact conformation on the 30S ribosomal subunit, similar to that induced by Initiation Factor IF1. This compaction was faster for Tig than Dem or Otc. Furthermore, all three tested tetracyclines affected IF1-bound 30S complexes. The dissociation rate constant of IF1 in early 30S complexes was 14-fold slower for Tig than Dem or Otc. Late 30S initiation complexes (30S pre-IC or IC) exhibited greater IF1 stabilization by Tig than for Dem and Otc. Tig and Otc delayed 50S joining to 30S initiation complexes (30S ICs). Remarkably, the presence of Tig considerably slowed the progression to translation elongation and retained IF1 in the resulting 70S initiation complex (70S IC). Molecular modeling of Tetracyclines bound to the 30S pre-IC and 30S IC indicated that the antibiotics binding site topography fluctuates along the initiation pathway. Mainly, 30S complexes show potential contacts between Dem or Tig with IF1, providing a structural rationale for the enhanced affinity of the antibiotics in the presence of the factor. Altogether, our data indicate that Tetracyclines inhibit translation initiation by allosterically perturbing the IF3 layout on the 30S, retaining IF1 during 70S IC formation, and slowing the transition toward translation elongation. Thus, this study describes a new complementary mechanism by which Tetracyclines may inhibit bacterial protein synthesis. © Copyright © 2021 Barrenechea, Vargas-Reyes, Quiliano and Milón.Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica - ConcytecengFrontiers Media S.A.Frontiers in Microbiologyinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/4.0/translation initiationantibiotic-1initiation factor-1ribosome-1tetracycline-1tigecycline-1https://purl.org/pe-repo/ocde/ford#3.01.02-1A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclinesinfo:eu-repo/semantics/articlereponame:CONCYTEC-Institucionalinstname:Consejo Nacional de Ciencia Tecnología e Innovacióninstacron:CONCYTEC20.500.12390/2954oai:repositorio.concytec.gob.pe:20.500.12390/29542024-05-30 16:12:27.635https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_14cbinfo:eu-repo/semantics/closedAccessmetadata only accesshttps://repositorio.concytec.gob.peRepositorio Institucional CONCYTECrepositorio@concytec.gob.pe#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#<Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="8725486b-a61f-4dd7-b1d2-37d27fa94517"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>A Complementary Mechanism of Bacterial mRNA Translation Inhibition by Tetracyclines</Title> <PublishedIn> <Publication> <Title>Frontiers in Microbiology</Title> </Publication> </PublishedIn> <PublicationDate>2021</PublicationDate> <DOI>https://doi.org/10.3389/fmicb.2021.682682</DOI> <SCP-Number>2-s2.0-85109589171</SCP-Number> <Authors> <Author> <DisplayName>Barrenechea V.</DisplayName> <Person id="rp08357" /> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> <Author> <DisplayName>Vargas-Reyes M.</DisplayName> <Person id="rp08358" /> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> <Author> <DisplayName>Quiliano M.</DisplayName> <Person id="rp08359" /> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> <Author> <DisplayName>Milón P.</DisplayName> <Person id="rp05844" /> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Frontiers Media S.A.</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>https://creativecommons.org/licenses/by-nc-nd/4.0/</License> <Keyword>translation initiation</Keyword> <Keyword>antibiotic</Keyword> <Keyword>initiation factor</Keyword> <Keyword>ribosome</Keyword> <Keyword>tetracycline</Keyword> <Keyword>tigecycline</Keyword> <Abstract>Tetracycline has positively impacted human health as well as the farming and animal industries. Its extensive usage and versatility led to the spread of resistance mechanisms followed by the development of new variants of the antibiotic. Tetracyclines inhibit bacterial growth by impeding the binding of elongator tRNAs to the ribosome. However, a small number of reports indicated that Tetracyclines could also inhibit translation initiation, yet the molecular mechanism remained unknown. Here, we use biochemical and computational methods to study how Oxytetracycline (Otc), Demeclocycline (Dem), and Tigecycline (Tig) affect the translation initiation phase of protein synthesis. Our results show that all three Tetracyclines induce Initiation Factor IF3 to adopt a compact conformation on the 30S ribosomal subunit, similar to that induced by Initiation Factor IF1. This compaction was faster for Tig than Dem or Otc. Furthermore, all three tested tetracyclines affected IF1-bound 30S complexes. The dissociation rate constant of IF1 in early 30S complexes was 14-fold slower for Tig than Dem or Otc. Late 30S initiation complexes (30S pre-IC or IC) exhibited greater IF1 stabilization by Tig than for Dem and Otc. Tig and Otc delayed 50S joining to 30S initiation complexes (30S ICs). Remarkably, the presence of Tig considerably slowed the progression to translation elongation and retained IF1 in the resulting 70S initiation complex (70S IC). Molecular modeling of Tetracyclines bound to the 30S pre-IC and 30S IC indicated that the antibiotics binding site topography fluctuates along the initiation pathway. Mainly, 30S complexes show potential contacts between Dem or Tig with IF1, providing a structural rationale for the enhanced affinity of the antibiotics in the presence of the factor. Altogether, our data indicate that Tetracyclines inhibit translation initiation by allosterically perturbing the IF3 layout on the 30S, retaining IF1 during 70S IC formation, and slowing the transition toward translation elongation. Thus, this study describes a new complementary mechanism by which Tetracyclines may inhibit bacterial protein synthesis. © Copyright © 2021 Barrenechea, Vargas-Reyes, Quiliano and Milón.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication> -1 |
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13.413352 |
Nota importante:
La información contenida en este registro es de entera responsabilidad de la institución que gestiona el repositorio institucional donde esta contenido este documento o set de datos. El CONCYTEC no se hace responsable por los contenidos (publicaciones y/o datos) accesibles a través del Repositorio Nacional Digital de Ciencia, Tecnología e Innovación de Acceso Abierto (ALICIA).
La información contenida en este registro es de entera responsabilidad de la institución que gestiona el repositorio institucional donde esta contenido este documento o set de datos. El CONCYTEC no se hace responsable por los contenidos (publicaciones y/o datos) accesibles a través del Repositorio Nacional Digital de Ciencia, Tecnología e Innovación de Acceso Abierto (ALICIA).
