Proteolysis-targeting strategies in bacterial systems for functional studies of proteins and improvement of antibiotics

Principal Investigator: Maria Górna (Project partners: Ben Luisi and WPD Pharmaceuticals).

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional molecules targeting proteins for degradation. Eukaryotic PROTACs exploiting ligands of E3 ubiquitin ligases emerged as very potent drugs, due to their irreversible and recyclable mode of action. However, this approach has not yet been employed in bacteria, which lack the ubiquitin-proteasome pathway. We will establish whether an induced-proteolysis approach would be effective to down-regulate target endogenous proteins in bacteria, and engineer the molecular tools needed to do so. We will screen for suitable bacterial proteases and ligands, including known adaptor tags and degrons. Identified ligands will be validated in vitro and in bacteria. The resulting molecular tools will enable regulation of gene expression on the protein level for studies of protein function and drug action. Bacterial PROTACs could pave the way to create novel antibiotics, which is crucial in the era of increasing antimicrobial resistance.

Founding source:

Foundation for Polish Science - FIRST TEAM 5/2018

Proteolysis-targeting strategies in bacterial systems for functional studies of proteins and improvement of antibiotics

• PLN 2 099 970
• Feb 1st 2019 - Oct 31st 2022
• #POIR.04.04.00-00-5EC1/18-00
• Project PI: Maria Górna