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Homo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria

Author

Listed:
  • Lukas Junk

    (Saarland University)

  • Volker M. Schmiedel

    (Boehringer Ingelheim RCV GmbH & Co. KG)

  • Somraj Guha

    (Saarland University)

  • Katharina Fischel

    (Boehringer Ingelheim RCV GmbH & Co. KG)

  • Peter Greb

    (Boehringer Ingelheim RCV GmbH & Co. KG)

  • Kristin Vill

    (Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical Biology and Biotechnology)

  • Violetta Krisilia

    (Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical Biology and Biotechnology)

  • Lasse Geelen

    (Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical Biology and Biotechnology)

  • Klaus Rumpel

    (Boehringer Ingelheim RCV GmbH & Co. KG)

  • Parvinder Kaur

    (Foundation for Neglected Disease Research)

  • Ramya V. Krishnamurthy

    (Foundation for Neglected Disease Research)

  • Shridhar Narayanan

    (Foundation for Neglected Disease Research)

  • Radha Krishan Shandil

    (Foundation for Neglected Disease Research)

  • Mayas Singh

    (Foundation for Neglected Disease Research)

  • Christiane Kofink

    (Boehringer Ingelheim RCV GmbH & Co. KG)

  • Andreas Mantoulidis

    (Boehringer Ingelheim RCV GmbH & Co. KG)

  • Philipp Biber

    (Boehringer Ingelheim RCV GmbH & Co. KG)

  • Gerhard Gmaschitz

    (Boehringer Ingelheim RCV GmbH & Co. KG)

  • Uli Kazmaier

    (Saarland University)

  • Anton Meinhart

    (Research Institute of Molecular Pathology, Vienna BioCenter)

  • Julia Leodolter

    (Research Institute of Molecular Pathology, Vienna BioCenter)

  • David Hoi

    (Research Institute of Molecular Pathology, Vienna BioCenter)

  • Sabryna Junker

    (Research Institute of Molecular Pathology, Vienna BioCenter)

  • Francesca Ester Morreale

    (Research Institute of Molecular Pathology, Vienna BioCenter)

  • Tim Clausen

    (Research Institute of Molecular Pathology, Vienna BioCenter)

  • Rainer Kalscheuer

    (Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical Biology and Biotechnology)

  • Harald Weinstabl

    (Boehringer Ingelheim RCV GmbH & Co. KG)

  • Guido Boehmelt

    (Boehringer Ingelheim RCV GmbH & Co. KG)

Abstract

Antimicrobial resistance is a global health threat that requires the development of new treatment concepts. These should not only overcome existing resistance but be designed to slow down the emergence of new resistance mechanisms. Targeted protein degradation, whereby a drug redirects cellular proteolytic machinery towards degrading a specific target, is an emerging concept in drug discovery. We are extending this concept by developing proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery. The anti-Mycobacterium tuberculosis (Mtb) BacPROTACs are derived from cyclomarins which, when dimerized, generate compounds that recruit and degrade ClpC1. The resulting Homo-BacPROTACs reduce levels of endogenous ClpC1 in Mycobacterium smegmatis and display minimum inhibitory concentrations in the low micro- to nanomolar range in mycobacterial strains, including multiple drug-resistant Mtb isolates. The compounds also kill Mtb residing in macrophages. Thus, Homo-BacPROTACs that degrade ClpC1 represent a different strategy for targeting Mtb and overcoming drug resistance.

Suggested Citation

  • Lukas Junk & Volker M. Schmiedel & Somraj Guha & Katharina Fischel & Peter Greb & Kristin Vill & Violetta Krisilia & Lasse Geelen & Klaus Rumpel & Parvinder Kaur & Ramya V. Krishnamurthy & Shridhar Na, 2024. "Homo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46218-7
    DOI: 10.1038/s41467-024-46218-7
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    References listed on IDEAS

    as
    1. Débora Broch Trentini & Marcin Józef Suskiewicz & Alexander Heuck & Robert Kurzbauer & Luiza Deszcz & Karl Mechtler & Tim Clausen, 2016. "Arginine phosphorylation marks proteins for degradation by a Clp protease," Nature, Nature, vol. 539(7627), pages 48-53, November.
    2. Steven M. Banik & Kayvon Pedram & Simon Wisnovsky & Green Ahn & Nicholas M. Riley & Carolyn R. Bertozzi, 2020. "Lysosome-targeting chimaeras for degradation of extracellular proteins," Nature, Nature, vol. 584(7820), pages 291-297, August.
    3. Chiara Maniaci & Scott J. Hughes & Andrea Testa & Wenzhang Chen & Douglas J. Lamont & Sonia Rocha & Dario R. Alessi & Roberto Romeo & Alessio Ciulli, 2017. "Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
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