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Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida

Macrolides have been effective clinical antibiotics for over 70 years. They inhibit protein biosynthesis in bacterial pathogens by narrowing the nascent protein exit tunnel in the ribosome. The macrolide class of natural products consist of a macrolactone ring linked to one or more sugar molecules....

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Autores principales: Breiner-Goldstein, Elinor, Eyal, Zohar, Matzov, Donna, Halfon, Yehuda, Cimicata, Giuseppe, Baum, Moti, Rokney, Assaf, Ezernitchi, Analia V, Lowell, Andrew N, Schmidt, Jennifer J, Rozenberg, Haim, Zimmerman, Ella, Bashan, Anat, Valinsky, Lea, Anzai, Yojiro, Sherman, David H, Yonath, Ada
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450085/
https://www.ncbi.nlm.nih.gov/pubmed/34417608
http://dx.doi.org/10.1093/nar/gkab684
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author Breiner-Goldstein, Elinor
Eyal, Zohar
Matzov, Donna
Halfon, Yehuda
Cimicata, Giuseppe
Baum, Moti
Rokney, Assaf
Ezernitchi, Analia V
Lowell, Andrew N
Schmidt, Jennifer J
Rozenberg, Haim
Zimmerman, Ella
Bashan, Anat
Valinsky, Lea
Anzai, Yojiro
Sherman, David H
Yonath, Ada
author_facet Breiner-Goldstein, Elinor
Eyal, Zohar
Matzov, Donna
Halfon, Yehuda
Cimicata, Giuseppe
Baum, Moti
Rokney, Assaf
Ezernitchi, Analia V
Lowell, Andrew N
Schmidt, Jennifer J
Rozenberg, Haim
Zimmerman, Ella
Bashan, Anat
Valinsky, Lea
Anzai, Yojiro
Sherman, David H
Yonath, Ada
author_sort Breiner-Goldstein, Elinor
collection PubMed
description Macrolides have been effective clinical antibiotics for over 70 years. They inhibit protein biosynthesis in bacterial pathogens by narrowing the nascent protein exit tunnel in the ribosome. The macrolide class of natural products consist of a macrolactone ring linked to one or more sugar molecules. Most of the macrolides used currently are semi-synthetic erythromycin derivatives, composed of a 14- or 15-membered macrolactone ring. Rapidly emerging resistance in bacterial pathogens is among the most urgent global health challenges, which render many antibiotics ineffective, including next-generation macrolides. To address this threat and advance a longer-term plan for developing new antibiotics, we demonstrate how 16-membered macrolides overcome erythromycin resistance in clinically isolated Staphylococcus aureus strains. By determining the structures of complexes of the large ribosomal subunit of Deinococcus radiodurans (D50S) with these 16-membered selected macrolides, and performing anti-microbial studies, we identified resistance mechanisms they may overcome. This new information provides important insights toward the rational design of therapeutics that are effective against drug resistant human pathogens.
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spelling pubmed-84500852021-09-20 Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida Breiner-Goldstein, Elinor Eyal, Zohar Matzov, Donna Halfon, Yehuda Cimicata, Giuseppe Baum, Moti Rokney, Assaf Ezernitchi, Analia V Lowell, Andrew N Schmidt, Jennifer J Rozenberg, Haim Zimmerman, Ella Bashan, Anat Valinsky, Lea Anzai, Yojiro Sherman, David H Yonath, Ada Nucleic Acids Res Structural Biology Macrolides have been effective clinical antibiotics for over 70 years. They inhibit protein biosynthesis in bacterial pathogens by narrowing the nascent protein exit tunnel in the ribosome. The macrolide class of natural products consist of a macrolactone ring linked to one or more sugar molecules. Most of the macrolides used currently are semi-synthetic erythromycin derivatives, composed of a 14- or 15-membered macrolactone ring. Rapidly emerging resistance in bacterial pathogens is among the most urgent global health challenges, which render many antibiotics ineffective, including next-generation macrolides. To address this threat and advance a longer-term plan for developing new antibiotics, we demonstrate how 16-membered macrolides overcome erythromycin resistance in clinically isolated Staphylococcus aureus strains. By determining the structures of complexes of the large ribosomal subunit of Deinococcus radiodurans (D50S) with these 16-membered selected macrolides, and performing anti-microbial studies, we identified resistance mechanisms they may overcome. This new information provides important insights toward the rational design of therapeutics that are effective against drug resistant human pathogens. Oxford University Press 2021-08-20 /pmc/articles/PMC8450085/ /pubmed/34417608 http://dx.doi.org/10.1093/nar/gkab684 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Structural Biology
Breiner-Goldstein, Elinor
Eyal, Zohar
Matzov, Donna
Halfon, Yehuda
Cimicata, Giuseppe
Baum, Moti
Rokney, Assaf
Ezernitchi, Analia V
Lowell, Andrew N
Schmidt, Jennifer J
Rozenberg, Haim
Zimmerman, Ella
Bashan, Anat
Valinsky, Lea
Anzai, Yojiro
Sherman, David H
Yonath, Ada
Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida
title Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida
title_full Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida
title_fullStr Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida
title_full_unstemmed Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida
title_short Ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from Micromonospora griseorubida
title_sort ribosome-binding and anti-microbial studies of the mycinamicins, 16-membered macrolide antibiotics from micromonospora griseorubida
topic Structural Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450085/
https://www.ncbi.nlm.nih.gov/pubmed/34417608
http://dx.doi.org/10.1093/nar/gkab684
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