Tazobactam-Derived Glues Steer Bacterial DegP to Destroy TEM β-Lactamases
- Small molecules were found that bring TEM-type β-lactamases to the periplasmic protease DegP, so the resistance enzyme is destroyed rather than merely blocked.
- Tazobactam itself sped DegP-mediated turnover; adding linker-free dipeptide motifs common in DegP substrates boosted it further.
- With piperacillin, the optimized glues outperformed tazobactam against resistant E. coli and showed oral-compatible pharmacokinetics.
💡 Points Based on the abstract
Resistance enzymes are usually inhibited, which selects for escape variants; degradation only changes that if the glue also works on free enzyme, not just acylated TEM, given tazobactam's covalent mechanism. Linker-free dipeptides hint the enzyme is read as an ordinary DegP substrate. Activity against KPC and CTX-M would show how general the strategy is.
Molecular Glue Degraders of TEM β‐Lactamases by Periplasmic Protease DegP ↗