Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, MA, 02115, USA.
Nat Commun. 2024 May 14;15(1):4065. doi: 10.1038/s41467-024-48506-8.
Proteolysis-targeting chimeras (PROTACs) represent a new therapeutic modality involving selectively directing disease-causing proteins for degradation through proteolytic systems. Our ability to exploit targeted protein degradation (TPD) for antibiotic development remains nascent due to our limited understanding of which bacterial proteins are amenable to a TPD strategy. Here, we use a genetic system to model chemically-induced proximity and degradation to screen essential proteins in Mycobacterium smegmatis (Msm), a model for the human pathogen M. tuberculosis (Mtb). By integrating experimental screening of 72 protein candidates and machine learning, we find that drug-induced proximity to the bacterial ClpC1P1P2 proteolytic complex leads to the degradation of many endogenous proteins, especially those with disordered termini. Additionally, TPD of essential Msm proteins inhibits bacterial growth and potentiates the effects of existing antimicrobial compounds. Together, our results provide biological principles to select and evaluate attractive targets for future Mtb PROTAC development, as both standalone antibiotics and potentiators of existing antibiotic efficacy.
蛋白水解靶向嵌合体（PROTACs）代表了一种新的治疗模式，通过蛋白酶体系统选择性地将致病蛋白定向降解。由于我们对哪些细菌蛋白适合靶向蛋白降解（TPD）策略的理解有限，因此我们利用靶向蛋白降解（TPD）来开发抗生素的能力仍处于起步阶段。在这里，我们使用遗传系统来模拟化学诱导的接近和降解，以筛选分枝杆菌（Msm）中的必需蛋白，分枝杆菌是人类病原体结核分枝杆菌（Mtb）的模型。通过整合对 72 种蛋白质候选物的实验筛选和机器学习，我们发现药物诱导与细菌 ClpC1P1P2 蛋白酶复合物的接近导致许多内源性蛋白质的降解，特别是那些具有无序末端的蛋白质。此外，必需的 Msm 蛋白的 TPD 抑制细菌生长并增强现有抗菌化合物的作用。总之，我们的结果为选择和评估未来 Mtb PROTAC 开发的有吸引力的目标提供了生物学原理，既可以作为独立的抗生素，也可以增强现有抗生素的疗效。
