Dataset / Code: Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy
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Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy Harim I. Won1,#, Samuel Zinga1,#, Olga Kandror1, Tatos Akopian1, Ian D. Wolf1, Jessica T.P. Schweber1, Ernst W. Schmid2, Michael C. Chao1, Maya Waldor1, Eric J. Rubin1,*, Junhao Zhu1,3,* 1Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA. 2Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, Massachusetts 02115, USA. 3CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. #These authors contributed equally to this work. *Corresponding authors: zhujh@im.ac.cn (J.Z.), erubin@hsph.harvard.edu (E. J. R.) 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.
