2. Academic Validation
  3. Homo-BacPROTAC-induced degradation of ClpC1 as a strategy against drug-resistant mycobacteria

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

  • Nat Commun. 2024 Mar 5;15(1):2005. doi: 10.1038/s41467-024-46218-7.
Lukas Junk # 1,  Volker M Schmiedel # 2,  Somraj Guha 3,  Katharina Fischel 2,  Peter Greb 2,  Kristin Vill 4,  Violetta Krisilia 4,  Lasse van Geelen 4,  Klaus Rumpel 2,  Parvinder Kaur 5,  Ramya V Krishnamurthy 5,  Shridhar Narayanan 5,  Radha Krishan Shandil 5,  Mayas Singh 5,  Christiane Kofink 2,  Andreas Mantoulidis 2,  Philipp Biber 2,  Gerhard Gmaschitz 2,  Uli Kazmaier 3,  Anton Meinhart 6,  Julia Leodolter 6,  David Hoi 6,  Sabryna Junker 6,  Francesca Ester Morreale 6,  Tim Clausen 6,  Rainer Kalscheuer 4,  Harald Weinstabl 7,  Guido Boehmelt 8
Affiliations

Affiliations

  • 1 Organic Chemistry I, Saarland University, Campus Building C4.2, 66123, Saarbrücken, Germany. [email protected].
  • 2 Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer-Gasse 5-11, 1121, Vienna, Austria.
  • 3 Organic Chemistry I, Saarland University, Campus Building C4.2, 66123, Saarbrücken, Germany.
  • 4 Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Pharmaceutical Biology and Biotechnology, 40225, Düsseldorf, Germany.
  • 5 Foundation for Neglected Disease Research, Plot No. 20A, KIADB Industrial Area, Veerapura Village, Doddaballapur, Bengaluru, 561203, Karnataka, India.
  • 6 Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria.
  • 7 Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer-Gasse 5-11, 1121, Vienna, Austria. [email protected].
  • 8 Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer-Gasse 5-11, 1121, Vienna, Austria. [email protected].
  • # Contributed equally.
PMID: 38443338 DOI: 10.1038/s41467-024-46218-7
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.

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