Scientists Develop First-in-Class Bacterial PROTACs That Outperform Traditional Antibiotics Against Tuberculosis
Researchers have developed the first heterobifunctional bacterial proteolysis targeting chimeras (BacPROTACs) directed against an essential Mycobacterium tuberculosis protein, demonstrating markedly improved antimycobacterial activity compared to conventional inhibitors. The compounds target PptT, an essential TB protein, by repurposing existing inhibitors into degrader molecules that harness the bacterium's own protein disposal machinery. This establishes targeted protein degradation as a new mechanistic strategy for antibacterial drug discovery, potentially opening up a vast range of previously undruggable bacterial targets.
A study posted to bioRxiv describes the development of first-in-class BacPROTACs — heterobifunctional molecules that direct bacterial protein degradation machinery toward an essential Mycobacterium tuberculosis enzyme called 4'-phosphopantetheinyl transferase (PptT). Unlike conventional antibiotics that rely on occupancy-driven inhibition, BacPROTACs work by tagging target proteins for destruction, offering a mechanistically distinct approach. The researchers leveraged the modular architecture of BacPROTACs to repurpose existing PptT inhibitors, incorporating them into degrader compounds that showed markedly improved antimycobacterial activity. The team also developed an integrated in vitro and cellular characterisation pipeline to assess protein degradation in bacteria, which they propose could be applied to future BacPROTAC programmes. The work is significant because targeted protein degradation has been transformative in cancer drug discovery but has remained largely unexplored in antibacterial contexts, and this study provides a proof-of-concept framework for extending the approach to TB and potentially other bacterial pathogens.
What's missing
As a preprint, this work has not yet undergone peer review. Key limitations not addressed include in vivo efficacy and safety data, pharmacokinetic properties of the BacPROTAC compounds, potential for resistance development, and whether the approach is generalizable beyond PptT to other essential bacterial proteins.
What different sources said
- bioRxivCenter
BacPROTACs outperform inhibitors in Mycobacterium tuberculosis
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