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Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif

Antibiotics target key biological processes that include protein synthesis. Bacteria respond by developing resistance, which increases rapidly due to antibiotics overuse. Mupirocin, a clinically used natural antibiotic, inhibits isoleucyl-tRNA synthetase (IleRS), an enzyme that links isoleucine to i...

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Autores principales: Brkic, A., Leibundgut, M., Jablonska, J., Zanki, V., Car, Z., Petrovic Perokovic, V., Marsavelski, A., Ban, N., Gruic-Sovulj, I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10485003/
https://www.ncbi.nlm.nih.gov/pubmed/37679387
http://dx.doi.org/10.1038/s41467-023-41244-3
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author Brkic, A.
Leibundgut, M.
Jablonska, J.
Zanki, V.
Car, Z.
Petrovic Perokovic, V.
Marsavelski, A.
Ban, N.
Gruic-Sovulj, I.
author_facet Brkic, A.
Leibundgut, M.
Jablonska, J.
Zanki, V.
Car, Z.
Petrovic Perokovic, V.
Marsavelski, A.
Ban, N.
Gruic-Sovulj, I.
author_sort Brkic, A.
collection PubMed
description Antibiotics target key biological processes that include protein synthesis. Bacteria respond by developing resistance, which increases rapidly due to antibiotics overuse. Mupirocin, a clinically used natural antibiotic, inhibits isoleucyl-tRNA synthetase (IleRS), an enzyme that links isoleucine to its tRNA(Ile) for protein synthesis. Two IleRSs, mupirocin-sensitive IleRS1 and resistant IleRS2, coexist in bacteria. The latter may also be found in resistant Staphylococcus aureus clinical isolates. Here, we describe the structural basis of mupirocin resistance and unravel a mechanism of hyper-resistance evolved by some IleRS2 proteins. We surprisingly find that an up to 10(3)-fold increase in resistance originates from alteration of the HIGH motif, a signature motif of the class I aminoacyl-tRNA synthetases to which IleRSs belong. The structural analysis demonstrates how an altered HIGH motif could be adopted in IleRS2 but not IleRS1, providing insight into an elegant mechanism for coevolution of the key catalytic motif and associated antibiotic resistance.
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spelling pubmed-104850032023-09-09 Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif Brkic, A. Leibundgut, M. Jablonska, J. Zanki, V. Car, Z. Petrovic Perokovic, V. Marsavelski, A. Ban, N. Gruic-Sovulj, I. Nat Commun Article Antibiotics target key biological processes that include protein synthesis. Bacteria respond by developing resistance, which increases rapidly due to antibiotics overuse. Mupirocin, a clinically used natural antibiotic, inhibits isoleucyl-tRNA synthetase (IleRS), an enzyme that links isoleucine to its tRNA(Ile) for protein synthesis. Two IleRSs, mupirocin-sensitive IleRS1 and resistant IleRS2, coexist in bacteria. The latter may also be found in resistant Staphylococcus aureus clinical isolates. Here, we describe the structural basis of mupirocin resistance and unravel a mechanism of hyper-resistance evolved by some IleRS2 proteins. We surprisingly find that an up to 10(3)-fold increase in resistance originates from alteration of the HIGH motif, a signature motif of the class I aminoacyl-tRNA synthetases to which IleRSs belong. The structural analysis demonstrates how an altered HIGH motif could be adopted in IleRS2 but not IleRS1, providing insight into an elegant mechanism for coevolution of the key catalytic motif and associated antibiotic resistance. Nature Publishing Group UK 2023-09-07 /pmc/articles/PMC10485003/ /pubmed/37679387 http://dx.doi.org/10.1038/s41467-023-41244-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Brkic, A.
Leibundgut, M.
Jablonska, J.
Zanki, V.
Car, Z.
Petrovic Perokovic, V.
Marsavelski, A.
Ban, N.
Gruic-Sovulj, I.
Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif
title Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif
title_full Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif
title_fullStr Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif
title_full_unstemmed Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif
title_short Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif
title_sort antibiotic hyper-resistance in a class i aminoacyl-trna synthetase with altered active site signature motif
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10485003/
https://www.ncbi.nlm.nih.gov/pubmed/37679387
http://dx.doi.org/10.1038/s41467-023-41244-3
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