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Optimized arylomycins are a new class of Gram-negative antibiotics

Author

Listed:
  • Peter A. Smith

    (Genentech)

  • Michael F. T. Koehler

    (Genentech)

  • Hany S. Girgis

    (Genentech)

  • Donghong Yan

    (Genentech)

  • Yongsheng Chen

    (Wuxi AppTec)

  • Yuan Chen

    (Genentech)

  • James J. Crawford

    (Genentech)

  • Matthew R. Durk

    (Genentech)

  • Robert I. Higuchi

    (RQx Pharmaceuticals
    Retrovirox)

  • Jing Kang

    (Genentech)

  • Jeremy Murray

    (Genentech)

  • Prasuna Paraselli

    (RQx Pharmaceuticals
    Vertex)

  • Summer Park

    (Genentech)

  • Wilson Phung

    (Genentech)

  • John G. Quinn

    (Genentech)

  • Tucker C. Roberts

    (RQx Pharmaceuticals
    Aduro Biotech)

  • Lionel Rougé

    (Genentech)

  • Jacob B. Schwarz

    (Genentech
    FLX Bio)

  • Elizabeth Skippington

    (Genentech)

  • John Wai

    (Wuxi AppTec)

  • Min Xu

    (Genentech)

  • Zhiyong Yu

    (Wuxi AppTec)

  • Hua Zhang

    (Genentech)

  • Man-Wah Tan

    (Genentech)

  • Christopher E. Heise

    (Genentech
    Genentech)

Abstract

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins—a class of natural products with weak activity and limited spectrum—to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.

Suggested Citation

  • Peter A. Smith & Michael F. T. Koehler & Hany S. Girgis & Donghong Yan & Yongsheng Chen & Yuan Chen & James J. Crawford & Matthew R. Durk & Robert I. Higuchi & Jing Kang & Jeremy Murray & Prasuna Para, 2018. "Optimized arylomycins are a new class of Gram-negative antibiotics," Nature, Nature, vol. 561(7722), pages 189-194, September.
    • Handle: RePEc:nat:nature:v:561:y:2018:i:7722:d:10.1038_s41586-018-0483-6
    DOI: 10.1038/s41586-018-0483-6
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    Cited by:

    1. Chih-Wei Chen & Nadja Leimer & Egor A. Syroegin & Clémence Dunand & Zackery P. Bulman & Kim Lewis & Yury S. Polikanov & Maxim S. Svetlov, 2023. "Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Christopher J. Barden & Fan Wu & J. Pedro Fernandez-Murray & Erhu Lu & Shengguo Sun & Marcia M. Taylor & Annette L. Rushton & Jason Williams & Mahtab Tavasoli & Autumn Meek & Alla Siva Reddy & Lisa M., 2024. "Computer-aided drug design to generate a unique antibiotic family," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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