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

Sarah Batson, Cesira de Chiara, Vita Majce, Adrian J. Lloyd, Stanislav Gobec, Dean Rea, Vilmos Fülöp, Christopher W. Thoroughgood, Katie J. Simmons, Christopher G. Dowson, Colin W. G. Fishwick, Luiz Pedro S. de Carvalho () and David I. Roper ()
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Sarah Batson: School of Life Sciences, University of Warwick
Cesira de Chiara: Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute
Vita Majce: School of Life Sciences, University of Warwick
Adrian J. Lloyd: School of Life Sciences, University of Warwick
Stanislav Gobec: Faculty of Pharmacy, University of Ljubljana
Dean Rea: School of Life Sciences, University of Warwick
Vilmos Fülöp: School of Life Sciences, University of Warwick
Christopher W. Thoroughgood: School of Life Sciences, University of Warwick
Katie J. Simmons: School of Chemistry, University of Leeds
Christopher G. Dowson: School of Life Sciences, University of Warwick
Colin W. G. Fishwick: School of Chemistry, University of Leeds
Luiz Pedro S. de Carvalho: Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute
David I. Roper: School of Life Sciences, University of Warwick

Nature Communications, 2017, vol. 8, issue 1, 1-7

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02118-7

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