The new PROTAC, the first to degrade target protein in bacteria, could be used as a new antibacteria

Each year, bacterial infections kill hundreds of thousands of people, primarily in low- and middle-income countries. Given that only a few antibiotics have been approved during the last 50 years, the development of new antibiotics is also hampered by bacterial envelope permeability and a lack of specific targets. The rate at which pathogens develop resistance to existing drugs complicates the search for effective antibacterial agents even more. Given this unequal arms race, the resurgence of bacterial epidemics poses a significant threat, necessitating the development of novel infection-fighting strategies.

The induction of target protein degradation is a new concept in drug discovery. The ubiquitin-proteasome system is the primary pathway for intracellular protein degradation in eukaryotes, accounting for more than 80% of intracellular protein degradation.

The most prominent synthetic "degraders" are proteolytic targeting chimeras (PROTACs): bifunctional small molecules comprising an E3 ubiquitin ligase-binding moiety and a protein-of-target (POI)-binding chemical moiety. PROTAC facilitates POI ubiquitination and subsequent proteasomal degradation by bringing the E3 ligase into proximity with POI.

Protein degraders have a number of advantages over traditional inhibitors. For example, they have a higher degradation efficiency based on this catalytic mode. Furthermore, PROTACs can target virtually any cellular protein, and their two ports can be engineered modularly, allowing protein ligands to be engineered to design "degraders" for specific target proteins.

Despite this promise, PROTAC technology has so far been limited to eukaryotic ubiquitin labeling systems and has not been transferred to bacterial degradation pathways. Achieving target protein degradation within bacteria will provide attractive strategies for designing modulators of protein function and developing novel antibacterial agents.

In the journal Cell, Tim Clausen's laboratory at the Institute of Molecular Pathology in Vienna, Austria, and Markus Kaiser's laboratory at the University of Duisburg-Essen, Germany, published a study titled BacPROTACs mediate targeted protein degradation in bacteria. BacPROTAC, a novel small-molecule degrader, was developed in this study. The target protein was degraded in bacteria using the ClpCP protease degradation system, providing a new strategy for the development of antibacterial agents.

Although ubiquitination is only found in eukaryotic cells, bacteria also have a system for degrading proteins called ClpC that is similar to the ubiquitin-protease system, of which the recognition mechanism is considerably less complicated than the eukaryotic proteasome that recognizes intricate polyubiquitin signals. The target protein has an arginine residue with a phosphate group attached that is recognized as a degradation signal by the ClpCP protease, causing the target protein to degrade. ClpCP protease is present in Gram-positive bacteria and mycobacteria and has potential as a protein degradation element in bacterial protein degraders.

Theoretically, any protein in bacteria could be broken down by this modular design. As a proof-of-concept, the research team combined pArg (a ClpCNTD ligand) and biotin (a high-affinity mSA ligand) in vitro using monomeric streptavidin (mSA) as a model protein to create BacPROTAC-1 compound. At a concentration of 100?M, BacPROTAC-1 can bind to mSA and ClpCNTD to create an active ternary complex that can efficiently break down target proteins.

Overall, this research creates the bifunctional small molecule BacPROTAC, bringing the technology of targeted protein degradation to bacteria. BacPROTAC can also open up new avenues for the development of antibacterial agents with high selectivity and species specificity thanks to the advantages of its modular design. In addition, BacPROTAC has the potential to be a novel antibacterial agent and can be used to understand the function of bacterial proteins, resulting in the identification of new drug targets.

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