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

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 Narayanan, Radha Krishan Shandil, Mayas Singh, Christiane Kofink, Andreas Mantoulidis, Philipp Biber, Gerhard Gmaschitz, Uli Kazmaier, Anton Meinhart, Julia Leodolter, David Hoi, Sabryna Junker, Francesca Ester Morreale, Tim Clausen, Rainer Kalscheuer, Harald Weinstabl () and Guido Boehmelt ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46218-7

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