2. Academic Validation
  3. Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine

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

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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