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

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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. and Roper, David I. (2017) Inhibition of D-Ala : D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine. Nature Communications, 8 (1). 1939 . doi:10.1038/s41467-017-02118-7 ISSN 2041-1723.

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Official URL: http://dx.doi.org/10.1038/s41467-017-02118-7

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Abstract

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.

Item Type: Journal Article
Subjects: Q Science > QR Microbiology
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Alanine -- Synthesis -- Inhibitors, Antibiotics
Journal or Publication Title: Nature Communications
Publisher: Nature Publishing Group
ISSN: 2041-1723
Official Date: 5 December 2017
Dates:
DateEvent
5 December 2017Published
8 November 2017Accepted
Volume: 8
Number: 1
Article Number: 1939
DOI: 10.1038/s41467-017-02118-7
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 6 December 2017
Date of first compliant Open Access: 6 December 2017
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
PhD studentshipUniversity of Warwickhttp://dx.doi.org/10.13039/501100000741
G500643[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0701400[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G1100127[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
Grant 071998Wellcome Trusthttp://dx.doi.org/10.13039/100010269
Grant 068598Wellcome Trusthttp://dx.doi.org/10.13039/100010269
UNSPECIFIEDFrancis Crick Institutehttp://dx.doi.org/10.13039/100010438
FC001060Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
FC001060[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
FC001060Wellcome Trusthttp://dx.doi.org/10.13039/100004440
Grant No. L1-6745Javna Agencija za Raziskovalno Dejavnost RShttp://dx.doi.org/10.13039/501100004329
International Fellowship “For Women in Science”United Nations Educational, Scientific and Cultural Organizationhttp://dx.doi.org/10.13039/100005243
International Fellowship “For Women in Science”L'Oreal USAhttp://dx.doi.org/10.13039/100005137
UNSPECIFIEDAdvantage West Midlands (AWM)UNSPECIFIED

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