News Medical interviewed Natasha Bury, a PhD researcher at LifeArc, about the potential of targeted protein degradation as a new approach to address antimicrobial resistance, particularly in gram-negative bacteria. Bury’s research is supported by a fellowship from the Royal Commission for the Exhibition of 1851 and involves collaboration between LifeArc and the University of Glasgow.
Bury explained that targeted protein degradation is a relatively new concept in antibacterial drug discovery. Unlike conventional antibiotics, which typically work by inhibiting proteins, this method aims to eliminate harmful or disease-causing proteins altogether. She described the mechanism: "Targeted protein degradation is an approach that utilises this natural clearance machinery. It targets a molecule that binds to a harmful or disease-causing protein and delivers it to the clearance machinery where the protein is removed from the system altogether. Instead of simply blocking the protein’s activity, you are actively eliminating it."
She further noted how one degrader molecule can act on multiple copies of a target protein: "With targeted protein degradation, one molecule can remove multiple copies of a harmful protein. Once the protein is degraded, it is gone, and the degrader molecule is free to repeat the process."
Antimicrobial resistance poses increasing challenges as bacteria evolve mechanisms to evade current antibiotics. According to Bury, “The World Health Organization has predicted that by 2050, antimicrobial resistance could be responsible for up to 10 million deaths per year, overtaking cancer as a leading cause of death.” Gram-negative bacteria are especially difficult to treat due to their cell wall structure and efficient drug removal systems called efflux pumps.
Bury highlighted another important aspect: specificity. She said: "We can take advantage of these differences and look to design drugs that are specific to bacterial systems and not recognised in human cells. This specificity could help avoid toxicity issues and improve safety in the clinic." There may also be opportunities for designing degraders selective for certain bacterial groups or strains.
Despite its promise, there are technical barriers—particularly getting molecules into gram-negative bacteria—and currently no small molecules close to clinical use for recruiting bacterial systems in this way. Bury mentioned strategies such as Trojan horse approaches using peptides or iron receptors as possible solutions.
Resistance remains an unknown factor because targeted protein degradation in bacteria is still at proof-of-concept stage. However, since this strategy removes essential proteins rather than just inhibiting them, Bury suggested that “resistance to degraders could be slower than traditional antibiotics.”
Traditional drug discovery has focused on enzymes with well-defined binding sites; many other important proteins have been considered undruggable due to lack of such sites. Targeted degradation opens up new possibilities because it does not rely on binding site inhibition but instead focuses on removing proteins from cells.
Looking ahead at her own research plans within LifeArc’s collaborative environment, Bury stated: "Ideally, the target protein should be something the bacteria depend on for survival... I am also very interested in the idea of targeting resistance mechanisms themselves." She added: "If we could degrade proteins that confer antibiotic resistance, we might be able to resensitize bacteria to existing drugs."
LifeArc’s focus on translational science positions it well for moving early-stage discoveries toward clinical development. The ultimate goal would be more treatment options—including combination therapies—that address resistance both by targeting key bacterial functions and potentially removing resistance mechanisms themselves.
Reflecting on her career path so far she said: "From an early career perspective, it's incredible to be part of this... suddenly you find yourself working at the very beginning of a new discovery journey."
