We are interested in establishing a drug discovery strategy, known as targeted protein degradation, against pathogenic bacteria.
As opposed to the conventional approach of temporarily inhibiting proteins, targeted protein degradation technology relies on eliminating those proteins from cells altogether. Antibiotics that induce protein degradation in bacteria have the potential to expand the number of druggable protein targets and improve the efficacy of previously identified inhibitors.
Degrader antibiotics function by reprogramming the bacteria’s own waste-disposal pathways. These pathways normally keep the cell clear from unwanted or damaged proteins by degrading them. Through degrader antibiotics, we can interfere with cellular rules that determine which proteins to keep or dispose of. This results in bacterial cells causing self-damage, as proteins essential for survival would be irreversibly lost in the waste.
To establish degradation-reprogramming strategies in bacteria, our lab studies the structure, function and substrate preferences of bacterial proteolytic complexes combining biochemistry, cryo-electron microscopy and proteomics. We use high-throughput screening and chemical biology approaches to identify small molecule degraders and evaluate their activity against pathogens.
With degrader antibiotics expanding the number of tractable targets, we aim to counteract antimicrobial resistance, challenging the efficacy of currently available antibiotic treatments.