Pursuing Targeted Protein Degradation for Anti-TB Drug Development

Erick Strauss of Stellenbosch University in South Africa will develop small molecule anti-TB drugs that work by targeting bacterial proteins for degradation rather than inhibiting their activity. This strategy involves creating proteolysis targeting chimeras (PROTACs), linker proteins designed to bind specific bacterial proteins and target them for degradation by an endogenous intracellular protease. They will design and synthesize PROTACs against mycobacterial proteins of interest, then evaluate their activity using phenotypic assays with whole bacterial cells and using an ex vivo infected macrophage assay. They will characterize the mechanism of action of the PROTACs to assess their potency and guide iterative improvement. In parallel, they will also develop a screening platform, based on a cellular thermal shift assay (CETSA), to readily assess how well any PROTEC they design is able to penetrate mycobacterial cells and engage the specific target.