Targeted protein degradation is gaining traction as an innovative therapeutic strategy to combat notoriously difficult-to-treat illnesses. The development of this strategy is spearheaded by PROteolysis TArgeting Chimeras (PROTACs), bifunctional molecules with dual affinity for a target protein and ubiquitin-proteasome (UPS) regulating E3 ubiquitin ligases. Simultaneous engagement of the two protein components produces a ternary complex which facilitates ubiquitination of intracellular target proteins, leading to potent downstream degradation of the therapeutic target. This unique mechanism provides TPD agents with sustained activity against resistant disease pathologies, potent catalytic activity, and heightened target specificity. Currently, PROTAC agents treating resistant forms of cancer have exemplified these characteristics, leading to their successful advancement through Phase I and II clinical trials by biotech start-ups such as Arvinas, Kymera, Nurix and C4 Therapeutics. Excitingly, these advantages are mirrored even when exploiting other endogenous protein degradation systems, with early examples of autophagy- and lysosome-engaging degradation agents also displaying these favorable qualities.
At the same time, antimicrobial resistance (AMR) is a rapidly growing global health issue, with the lack of novel antimicrobial agents in clinical development failing to combat rapidly emerging strains of multidrug resistant bacteria. As of yet, a therapeutically viable strategy for achieving TPD in the context of antimicrobial drug discovery is yet to be conceived, however given their sustained activity against resistance mutations, applying TPD to design an antimicrobial agent could provide an effective response to the oncoming AMR crisis. This poster outlines a new project within the Blaskovich group which aims to translate the principles of Targeted Protein Degradation into the context of Antimicrobial Drug Discovery, in the hopes of using this unique approach to produce next-generation antibacterial agents to combat multidrug-resistant bacteria.