Targeted protein degradation for antibacterial discovery

Our research is focused on the discovery and development of novel small-molecule antibacterial agents, leveraging both traditional and emerging therapeutic modalities. My primary project centers on the design and application of bacterial Proteolysis Targeting Chimeras (BacPROTACs) as an innovative strategy to combat bacterial infections. PROTACs are bifunctional molecules composed of a protein-targeting moiety, a degradation-activating element, and a linker. Together, these components recruit the cellular degradation machinery to selectively eliminate essential proteins.

Unlike conventional inhibitors, PROTACs do not require the direct inhibition of protein function to exert their effects. Instead, they induce the degradation of the protein itself, allowing for the targeting of proteins that have traditionally been considered “undruggable.” This mechanism also offers the potential to overcome resistance mutations that would typically compromise inhibitor binding, positioning BacPROTACs as a promising new class of antibacterial agents.

In addition to this work, I am involved in a complementary project focused on the development of novel inhibitors of bacterial membrane trafficking. This effort targets the LolCDE complex, an essential component of the lipoprotein transport system in Gram-negative bacteria. As an inner membrane protein complex, LolCDE is more accessible to drug therapies compared to cytosolic targets, making it an attractive candidate for antibacterial development. We are currently characterizing a library of LolCDE inhibitors to expand the limited chemical space and mechanistic understanding of this novel target class.

Together, these projects aim to directly engage bacterial survival pathways and circumvent traditional resistance mechanisms.