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

Author

Listed:
  • 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
    Faculty of Pharmacy, University of Ljubljana)

  • 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)

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.

Suggested Citation

  • 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. Fishwi, 2017. "Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine," Nature Communications, Nature, vol. 8(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02118-7
    DOI: 10.1038/s41467-017-02118-7
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