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- Title
Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy.
- Authors
Won, Harim I.; Zinga, Samuel; Kandror, Olga; Akopian, Tatos; Wolf, Ian D.; Schweber, Jessica T. P.; Schmid, Ernst W.; Chao, Michael C.; Waldor, Maya; Rubin, Eric J.; Zhu, Junhao
- Abstract
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. Efforts to apply targeted protein degradation for antibiotic development are limited by our understanding of prokaryotic protein degradation. Here, the authors establish a chemical-genetic platform and predictive model to determine the degradation potential of essential mycobacterial proteins.
- Subjects
PROTEOLYSIS; BACTERIAL proteins; MYCOBACTERIUM smegmatis; MYCOBACTERIA; ANTIBIOTICS; BACTERIAL growth
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-48506-8