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Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

Author

Listed:
  • Anh T. Tran

    (School of Chemistry, The University of Sydney)

  • Emma E. Watson

    (School of Chemistry, The University of Sydney)

  • Venugopal Pujari

    (Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University)

  • Trent Conroy

    (School of Chemistry, The University of Sydney)

  • Luke J. Dowman

    (School of Chemistry, The University of Sydney)

  • Andrew M. Giltrap

    (School of Chemistry, The University of Sydney)

  • Angel Pang

    (Centenary Institute and Sydney Medical School, The University of Sydney)

  • Weng Ruh Wong

    (University of California)

  • Roger G. Linington

    (University of California
    Simon Fraser University)

  • Sebabrata Mahapatra

    (Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University)

  • Jessica Saunders

    (Centre for Drug Candidate Optimisation, Monash University)

  • Susan A. Charman

    (Centre for Drug Candidate Optimisation, Monash University)

  • Nicholas P. West

    (School of Chemistry and Molecular Biosciences, University of Queensland)

  • Timothy D. H. Bugg

    (University of Warwick)

  • Julie Tod

    (School of Life Sciences, University of Warwick)

  • Christopher G. Dowson

    (School of Life Sciences, University of Warwick)

  • David I. Roper

    (School of Life Sciences, University of Warwick)

  • Dean C. Crick

    (Mycobacteria Research Laboratories, Immunology and Pathology, Colorado State University)

  • Warwick J. Britton

    (Centenary Institute and Sydney Medical School, The University of Sydney)

  • Richard J. Payne

    (School of Chemistry, The University of Sydney)

Abstract

Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.

Suggested Citation

  • Anh T. Tran & Emma E. Watson & Venugopal Pujari & Trent Conroy & Luke J. Dowman & Andrew M. Giltrap & Angel Pang & Weng Ruh Wong & Roger G. Linington & Sebabrata Mahapatra & Jessica Saunders & Susan A, 2017. "Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis," Nature Communications, Nature, vol. 8(1), pages 1-9, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14414
    DOI: 10.1038/ncomms14414
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