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

DOI: 10.1038/s41467-017-02118-7 DOI Help

Authors: Sarah Batson (University of Warwick) , Cesira De Chiara (The Francis Crick Institute) , Vita Majce (University of Warwick) , Adrian J. Lloyd (University of Warwick) , Stanislav Gobec (University of Ljubljana) , Dean Rea (University of Warwick) , Vilmos Fulop (University of Warwick) , Christopher Thoroughgood (University of Warwick) , Katie J. Simmons (University of Leeds) , Christopher G. Dowson (University of Warwick) , Colin W. G. Fishwick (University of Leeds) , Luiz Pedro S. De Carvalho (The Francis Crick Institute) , David I. Roper (University of Warwick)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 8

State: Published (Approved)
Published: December 2017

Open Access Open Access

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.

Journal Keywords: Antibiotics; X-ray crystallography

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Documents:
s41467-017-02118-7.pdf