Enabling antibiotics discovery by targeted protein degradation

靶向蛋白质降解技术为基础研究和药物发现提供了独特的机会。然而，由于原核细胞中缺乏泛素-蛋白酶体系统，因此在细菌中的应用尚未探索。最近的一项研究（Morreale FE et al. Cell，2022）通过劫持ClpCP蛋白水解复合物将这一概念转化为细菌，这对革兰氏阳性菌和分枝杆菌中的蛋白质质量控制至关重要。在此基础上，我们的目标是扩大细菌中靶向蛋白质降解方式的范围，确定利用不同细菌蛋白水解复合物降解细菌自身必需蛋白质的新型抗生素。

Targeted protein degradation technology offers unique opportunities for basic research and drug discovery. Yet application in bacteria has remained unexplored, due to the lack of a ubiquitin-proteasome system in prokaryotic cells. A recent study (Morreale FE et al. Cell, 2022) has now translated the concept to bacteria by hijacking ClpCP proteolytic complexes, essential for protein quality control in Gram-positives and mycobacteria. On this basis, we aim to expand the scope of targeted protein degradation modalities in bacteria, identifying novel antibiotics that harness different bacterial proteolytic complexes to degrade bacteria's own essential proteins.