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Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP

Author

Listed:
  • Bingyan Wei

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Tao Zhang

    (Chinese Academy of Sciences)

  • Pengyu Wang

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yihui Pan

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jiahui Li

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Weizhong Chen

    (ShanghaiTech University)

  • Min Zhang

    (Tongji University School of Medicine)

  • Quanjiang Ji

    (ShanghaiTech University)

  • Wenjuan Wu

    (Tongji University School of Medicine)

  • Lefu Lan

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jianhua Gan

    (Fudan University)

  • Cai-Guang Yang

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

The emergence of methicillin-resistant Staphylococcus aureus isolates highlights the urgent need to develop more antibiotics. ClpP is a highly conserved protease regulated by ATPases in bacteria and in mitochondria. Aberrant activation of bacterial ClpP is an alternative method of discovering antibiotics, while it remains difficult to develop selective Staphylococcus aureus ClpP activators that can avoid disturbing Homo sapiens ClpP functions. Here, we use a structure-based design to identify (R)- and (S)-ZG197 as highly selective Staphylococcus aureus ClpP activators. The key structural elements in Homo sapiens ClpP, particularly W146 and its joint action with the C-terminal motif, significantly contribute to the discrimination of the activators. Our selective activators display wide antibiotic properties towards an array of multidrug-resistant staphylococcal strains in vitro, and demonstrate promising antibiotic efficacy in zebrafish and murine skin infection models. Our findings indicate that the species-specific activators of Staphylococcus aureus ClpP are exciting therapeutic agents to treat staphylococcal infections.

Suggested Citation

  • Bingyan Wei & Tao Zhang & Pengyu Wang & Yihui Pan & Jiahui Li & Weizhong Chen & Min Zhang & Quanjiang Ji & Wenjuan Wu & Lefu Lan & Jianhua Gan & Cai-Guang Yang, 2022. "Anti-infective therapy using species-specific activators of Staphylococcus aureus ClpP," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34753-0
    DOI: 10.1038/s41467-022-34753-0
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    References listed on IDEAS

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    1. Yoav Kaplan & Shaked Reich & Elyaqim Oster & Shani Maoz & Irit Levin-Reisman & Irine Ronin & Orit Gefen & Oded Agam & Nathalie Q. Balaban, 2021. "Observation of universal ageing dynamics in antibiotic persistence," Nature, Nature, vol. 600(7888), pages 290-294, December.
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    4. B. P. Conlon & E. S. Nakayasu & L. E. Fleck & M. D. LaFleur & V. M. Isabella & K. Coleman & S. N. Leonard & R. D. Smith & J. N. Adkins & K. Lewis, 2013. "Activated ClpP kills persisters and eradicates a chronic biofilm infection," Nature, Nature, vol. 503(7476), pages 365-370, November.
    5. Malte Gersch & Kirsten Famulla & Maria Dahmen & Christoph Göbl & Imran Malik & Klaus Richter & Vadim S. Korotkov & Peter Sass & Helga Rübsamen-Schaeff & Tobias Madl & Heike Brötz-Oesterhelt & Stephan , 2015. "AAA+ chaperones and acyldepsipeptides activate the ClpP protease via conformational control," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
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    Cited by:

    1. Lin-Lin Zhou & Tao Zhang & Yun Xue & Chuan Yue & Yihui Pan & Pengyu Wang & Teng Yang & Meixia Li & Hu Zhou & Kan Ding & Jianhua Gan & Hongbin Ji & Cai-Guang Yang, 2023. "Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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