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A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens

Author

Listed:
  • Kade D. Roberts

    (Monash University)

  • Yan Zhu

    (Monash University)

  • Mohammad A. K. Azad

    (Monash University)

  • Mei-Ling Han

    (Monash University)

  • Jiping Wang

    (Monash University)

  • Lynn Wang

    (Monash University)

  • Heidi H. Yu

    (Monash University)

  • Andrew S. Horne

    (Monash University)

  • Jo-Anne Pinson

    (Monash University)

  • David Rudd

    (Monash University
    Monash University)

  • Nicolas H. Voelcker

    (Monash University
    Monash University)

  • Nitin A. Patil

    (Monash University)

  • Jinxin Zhao

    (Monash University)

  • Xukai Jiang

    (Monash University)

  • Jing Lu

    (Monash University)

  • Ke Chen

    (Monash University)

  • Olga Lomovskaya

    (Qpex Biopharma, Inc.)

  • Scott J. Hecker

    (Qpex Biopharma, Inc.)

  • Philip E. Thompson

    (Monash University)

  • Roger L. Nation

    (Monash University)

  • Michael N. Dudley

    (Qpex Biopharma, Inc.)

  • David C. Griffith

    (Qpex Biopharma, Inc.)

  • Tony Velkov

    (Monash University
    University of Melbourne)

  • Jian Li

    (Monash University)

Abstract

The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colistin suffer from major issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure in the lungs) and efficacy (negligible activity against pulmonary infections) that have severely limited their clinical utility. Here we employ chemical biology to systematically optimize multiple non-conserved positions in the polymyxin scaffold, and successfully disconnect the therapeutic efficacy from the toxicity to develop a new synthetic lipopeptide, structurally and pharmacologically distinct from polymyxin B and colistin. This resulted in the clinical candidate F365 (QPX9003) with superior safety and efficacy against lung infections caused by top-priority MDR pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae.

Suggested Citation

  • Kade D. Roberts & Yan Zhu & Mohammad A. K. Azad & Mei-Ling Han & Jiping Wang & Lynn Wang & Heidi H. Yu & Andrew S. Horne & Jo-Anne Pinson & David Rudd & Nicolas H. Voelcker & Nitin A. Patil & Jinxin Z, 2022. "A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29234-3
    DOI: 10.1038/s41467-022-29234-3
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    References listed on IDEAS

    as
    1. Eric D. Brown & Gerard D. Wright, 2016. "Antibacterial drug discovery in the resistance era," Nature, Nature, vol. 529(7586), pages 336-343, January.
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    Cited by:

    1. Kerry R. Buchholz & Mike Reichelt & Matthew C. Johnson & Sarah J. Robinson & Peter A. Smith & Steven T. Rutherford & John G. Quinn, 2024. "Potent activity of polymyxin B is associated with long-lived super-stoichiometric accumulation mediated by weak-affinity binding to lipid A," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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