Overcoming the Unexpected Functional Inversion of a PqsR Antagonist in Pseudomonas aeruginosa: An In Vivo Potent Antivirulence Agent Targeting pqs Quorum Sensing

Authors

  • Cenbin Lu,

    1. Helmholtz-Institute for Pharmaceutical Research Saarland & Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany)
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    • These authors contributed equally to this work.

  • Christine K. Maurer,

    1. Helmholtz-Institute for Pharmaceutical Research Saarland & Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany)
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    • These authors contributed equally to this work.

  • Benjamin Kirsch,

    1. Helmholtz-Institute for Pharmaceutical Research Saarland & Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany)
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  • Dr. Anke Steinbach,

    Corresponding author
    1. Helmholtz-Institute for Pharmaceutical Research Saarland & Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany)
    • Helmholtz-Institute for Pharmaceutical Research Saarland & Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany)

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  • Prof. Dr. Rolf W. Hartmann

    Corresponding author
    1. Helmholtz-Institute for Pharmaceutical Research Saarland & Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany)
    • Helmholtz-Institute for Pharmaceutical Research Saarland & Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, 66123 Saarbrücken (Germany)

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  • We thank Drs. Daniele Bano and Kostoula Troullinaki (German Center for Neurodegenerative Diseases, Bonn, Germany) for providing C. elegans, Dr. Matthew Wand (Health Protection Agency, Salisbury, UK) for valuable advice regarding the G. mellonella infection model, and Dr. Andrea Braunshausen for helpful discussions. pqs=Pseudomonas quinolone signal.

Abstract

The virulence regulator PqsR of Pseudomonas aeruginosa is considered as an attractive target for attenuating the bacterial pathogenicity without eliciting resistance. However, despite efforts and desires, no promising PqsR antagonist has been discovered thus far. Now, a surprising functionality change of a highly affine PqsR antagonist in P. aeruginosa is revealed, which is mediated by a bacterial signal molecule synthase and responsible for low cellular potency. Blockade of the susceptible position led to the discovery of the first antivirulence compound that is potent in vivo and targets PqsR, thus providing a proof of concept for this novel antivirulence therapy.

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