Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy

Harim I. Won, Samuel Zinga, Olga Kandror, Tatos Akopian, Ian D. Wolf, Jessica T. P. Schweber, Ernst W. Schmid, Michael C. Chao, Maya Waldor, Eric J. Rubin () and Junhao Zhu ()
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Harim I. Won: Harvard T.H. Chan School of Public Health
Samuel Zinga: Harvard T.H. Chan School of Public Health
Olga Kandror: Harvard T.H. Chan School of Public Health
Tatos Akopian: Harvard T.H. Chan School of Public Health
Ian D. Wolf: Harvard T.H. Chan School of Public Health
Jessica T. P. Schweber: Harvard T.H. Chan School of Public Health
Ernst W. Schmid: Blavatnik Institute
Michael C. Chao: Harvard T.H. Chan School of Public Health
Maya Waldor: Harvard T.H. Chan School of Public Health
Eric J. Rubin: Harvard T.H. Chan School of Public Health
Junhao Zhu: Harvard T.H. Chan School of Public Health

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48506-8

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