Author: Schwechel, Kristin ; Kalscheuer, Rainer ; Guha, Somraj ; Kleine, Stefan ; Payne, Richard J. ; Hartl, Markus ; Kaiser, Markus ; Meinhart, Anton ; Clausen, Tim ; Weinstabl, Harald ; Schmiedel, Volker M. ; Morreale, Francesca Ester ; Junker, Sabryna ; Kaschani, Farnusch ; Fischel, Katharina ; Junk, Lukas ; van Geelen, Lasse ; Boehmelt, Guido ; Rumpel, Klaus ; Hawkins, Paige M. E. ; Kazmaier, Uli ; Leodolter, Julia ; Hoi, David M. ; Podlesainski, David

The ClpC1:ClpP1P2 protease is a core component of the proteostasis system in mycobacteria.To improve the efficacy of antitubercular agents targeting the Clp protease, we characterized the mechanism of the antibiotics cyclomarin A and ecumicin.Quant. proteomics revealed that the antibiotics cause massive proteome imbalances, including upregulation of two unannotated yet conserved stress response factors, ClpC2 and ClpC3.These proteins likely protect the Clp protease from excessive amounts of misfolded proteins or from cyclomarin A, which we show to mimic damaged proteins.To overcome the Clp security system, we developed a BacPROTAC that induces degradation of ClpC1 together with its ClpC2 caretaker.The dual Clp degrader, built from linked cyclomarin A heads, was highly efficient in killing pathogenic Mycobacterium tuberculosis, with >100-fold increased potency over the parent antibiotic.Together, our data reveal Clp scavenger proteins as important proteostasis safeguards and highlight the potential of BacPROTACs as future antibiotics.

03 Apr 2023·Expert Opinion on Drug Discovery

PROTAC antibiotics: the time is now

Article

Author: Dick, Thomas ; Sarathy, Jickky Palmae ; Go, Mei-Lin ; Aldrich, Courtney C.

INTRODUCTIONNovel antibiotics are needed to keep antibiotic resistance at bay and to improve treatment of the many drug-susceptible infections for which current therapies achieve poor cure rates. While revolutionizing human therapeutics, the concept of targeted protein degradation (TPD) by bifunctional proteolysis targeting chimeras (PROTACs) has not yet been applied to the discovery of antibiotics. A major obstacle precluding successful translation of this strategy to antibiotic development is that bacteria lack the E3 ligase-proteasome system exploited by human PROTACs to facilitate target degradation.AREAS COVEREDThe authors describe the serendipitous discovery of the first monofunctional target-degrading antibiotic pyrazinamide, supporting TPD as a viable and novel approach in antibiotic discovery. They then discuss the rational design, mechanism, and activity of the first bifunctional antibacterial target degrader BacPROTAC, enabling a generalizable approach to TPD in bacteria.EXPERT OPINIONBacPROTACs demonstrate that linking a target directly to a bacterial protease complex can promote target degradation. BacPROTACs successfully bypass the 'middleman' E3 ligase, providing an entry strategy for the generation of antibacterial PROTACs. We speculate that antibacterial PROTACs will not only expand the target space but may also improve treatment by allowing dosage reduction, stronger bactericidal activity and activity against drug-tolerant 'persisters.'

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Preclinical	AT	Vienna Biocenter	26 Apr 2023
Tuberculosis	Preclinical	CN	Boehringer Ingelheim Shanghai Pharmaceuticals Co. Ltd.	26 Apr 2023

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