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

  • Nat Commun. 2017 Dec 5;8(1):1939. doi: 10.1038/s41467-017-02118-7.
Sarah Batson  1 ,  Cesira de Chiara  2 ,  Vita Majce  1  3 ,  Adrian J Lloyd  1 ,  Stanislav Gobec  3 ,  Dean Rea  1 ,  Vilmos Fülöp  1 ,  Christopher W Thoroughgood  1 ,  Katie J Simmons  4 ,  Christopher G Dowson  1 ,  Colin W G Fishwick  4 ,  Luiz Pedro S de Carvalho  5 ,  David I Roper  6
Affiliations
  • 1. School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK.
  • 2. Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, NW1 1AT, London, UK.
  • 3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000, Ljubljana, Slovenia.
  • 4. School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
  • 5. Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute, NW1 1AT, London, UK. [email protected].
  • 6. School of Life Sciences, University of Warwick, Coventry CV4 7AL, UK. [email protected].
PMID: 29208891 DOI: 10.1038/s41467-017-02118-7
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.

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