Targeting Proteostasis for Synergistic Interactions

Protein homeostasis is vital for bacterial survival, regulated during synthesis and through systems ensuring proper protein folding and function. The project explores synergies in proteostasis, investigating if mechanisms observed at the ribosome extend to translation and protein degradation in mycobacteria. Notably, the Clp system, crucial for protein quality control, is unexpectedly essential for in vitro growth under optimal conditions in mycobacteria. The study reveals synergies, such as rifampin with cell wall biosynthesis and peptidyl-tRNA hydrolase (Pth) with macrolide antibiotics, suggesting interconnected pathways. 

Image - Cryo-EM of Mtb ribosome in complex with the inhibitors capreomycin (CPM) and LZD-114

Inhibitory compounds targeting the Clp system are developed, with promising in vitro and murine infection activities.  At TBSGC, we aim to identify pathways and targets interacting with Pth, Clp, and other protein homeostasis components through genetic, structural, and chemical experiments. Additionally, we will explore using the Clp system in a proteolysis targeting chimera (PROTAC) strategy to degrade critical proteins. This approach, leveraging ligands to bind instead of inhibiting, is ideal for targeting proteins with unknown functions, including membrane proteins highlighted in another project.

Image - Cryo-EM of Mtb ribosome in complex with the regulatory factor MtbEttA at different ATP states.

Our fundamental aims for this program are :

  • Identify, characterize, and optimize small molecules that inhibit prioritized protein quality control targets
  • Develop a targeted protein degradation strategy using molecules that recruit to ClpX
  • Identify key proteins involved in proteostasis that synergize with known and new drugs and determine mechanisms that underlie synergy.