Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine

D-cycloserine is an antibiotic which targets sequential bacterial cell wall peptidoglycan biosynthesis enzymes: alanine racemase and D-alanine:D-alanine ligase. By a combination of structural, chemical and mechanistic studies here we show that the inhibition of D-alanine:D-alanine ligase by the anti...

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Autores principales: Batson, Sarah, de Chiara, Cesira, Majce, Vita, Lloyd, Adrian J., Gobec, Stanislav, Rea, Dean, Fülöp, Vilmos, Thoroughgood, Christopher W., Simmons, Katie J., Dowson, Christopher G., Fishwick, Colin W. G., de Carvalho, Luiz Pedro S., Roper, David I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717164/
https://www.ncbi.nlm.nih.gov/pubmed/29208891
http://dx.doi.org/10.1038/s41467-017-02118-7
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author Batson, Sarah
de Chiara, Cesira
Majce, Vita
Lloyd, Adrian J.
Gobec, Stanislav
Rea, Dean
Fülöp, Vilmos
Thoroughgood, Christopher W.
Simmons, Katie J.
Dowson, Christopher G.
Fishwick, Colin W. G.
de Carvalho, Luiz Pedro S.
Roper, David I.
author_facet Batson, Sarah
de Chiara, Cesira
Majce, Vita
Lloyd, Adrian J.
Gobec, Stanislav
Rea, Dean
Fülöp, Vilmos
Thoroughgood, Christopher W.
Simmons, Katie J.
Dowson, Christopher G.
Fishwick, Colin W. G.
de Carvalho, Luiz Pedro S.
Roper, David I.
author_sort Batson, Sarah
collection PubMed
description D-cycloserine is an antibiotic which targets sequential bacterial cell wall peptidoglycan biosynthesis enzymes: alanine racemase and D-alanine:D-alanine ligase. By a combination of structural, chemical and mechanistic studies here we show that the inhibition of D-alanine:D-alanine ligase by the antibiotic D-cycloserine proceeds via a distinct phosphorylated form of the drug. This mechanistic insight reveals a bimodal mechanism of action for a single antibiotic on different enzyme targets and has significance for the design of future inhibitor molecules based on this chemical structure.
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spelling pubmed-57171642017-12-08 Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine Batson, Sarah de Chiara, Cesira Majce, Vita Lloyd, Adrian J. Gobec, Stanislav Rea, Dean Fülöp, Vilmos Thoroughgood, Christopher W. Simmons, Katie J. Dowson, Christopher G. Fishwick, Colin W. G. de Carvalho, Luiz Pedro S. Roper, David I. Nat Commun Article D-cycloserine is an antibiotic which targets sequential bacterial cell wall peptidoglycan biosynthesis enzymes: alanine racemase and D-alanine:D-alanine ligase. By a combination of structural, chemical and mechanistic studies here we show that the inhibition of D-alanine:D-alanine ligase by the antibiotic D-cycloserine proceeds via a distinct phosphorylated form of the drug. This mechanistic insight reveals a bimodal mechanism of action for a single antibiotic on different enzyme targets and has significance for the design of future inhibitor molecules based on this chemical structure. Nature Publishing Group UK 2017-12-05 /pmc/articles/PMC5717164/ /pubmed/29208891 http://dx.doi.org/10.1038/s41467-017-02118-7 Text en © The Author(s) 2017 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Batson, Sarah
de Chiara, Cesira
Majce, Vita
Lloyd, Adrian J.
Gobec, Stanislav
Rea, Dean
Fülöp, Vilmos
Thoroughgood, Christopher W.
Simmons, Katie J.
Dowson, Christopher G.
Fishwick, Colin W. G.
de Carvalho, Luiz Pedro S.
Roper, David I.
Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine
title Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine
title_full Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine
title_fullStr Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine
title_full_unstemmed Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine
title_short Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine
title_sort inhibition of d-ala:d-ala ligase through a phosphorylated form of the antibiotic d-cycloserine
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717164/
https://www.ncbi.nlm.nih.gov/pubmed/29208891
http://dx.doi.org/10.1038/s41467-017-02118-7
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