Dr Ian Liddle
Development of PROTAC-antibiotics to mediate targeted protein degredation in drug resistant bacteria
Project Summary
Dr Ian Liddle’s research focusses on developing novel strategies to tackle the growing national and international crisis of antimicrobial resistance (AMR). New drugs and novel strategies are urgently needed to combat AMR before therapeutic options are exhausted. All living cells, bacteria and eukaryotic cells, have intracellular waste disposable systems that functions to degrade and eliminate waste proteins. A recent drug discovery strategy is to hijack a cells’ waste disposable machinery and induce target protein degradation (TPD) – the degradation of a specific disease-causing protein. Unlike a conventional drug that only inhibits a protein, one benefit of TPD is that it eliminates a protein function entirely.
A PROteolysis TArgeting Chimeras (PROTACs) is a two-headed small molecule ligand that can induce TPD. A PROTAC binds simultaneously to the target protein and to the cells degradation machinery, which results in the TPD and regeneration of the PROTAC molecule. The PROTAC strategy has proven extremely successful in oncology with several drug candidates now in clinical trials. However, bacteria and human (eukaryotic) cells have evolved different mechanisms to eliminate waste proteins. Bacteria rely on proteases to degrade proteins, such as the ClpXP protease complex. An unexplored strategy for TPD in bacteria is to hijack the ClpXP protease complex to produce a bacterial-PROTAC. A bacterial-PROTAC can be produced by connecting a ClpXP protease ligand to a known intracellular target protein ligand. The target protein ligand can bind to an essential protein, which would result in the protein degradation. Bacterial-PROTACs represent an unmet strategy to tackle the growing threat of AMR and as
new paradigm for antibiotic drug discovery. Ian will begin the chemical organic synthesis of bacterial-PROTACs followed by the microbiological testing against pathogenic bacterial strains. To further elucidate the bacterial-PROTAC mechanism of action, Ian will conduct western blotting and size exclusion chromatography on lead compounds.
Figure 1. A: Schematic of protein degradation mediated via the ClpXP protease. Two proteins, the ATP-unfoldase and ClpP peptidase associate to form ClpXP protease complex.
The ATP unfoldase recognises unfolded proteins and/or specific amino acid sequences and channels them through the ClpP peptidase for degradation. B: Bacterial-PROTACs will target the ClpXP protease using a recognisable peptide sequence.
Career Support Funding
With the career-development funding provided by the award, Dr Liddle will attend the Royal Society of Chemistry Targeted Protein Degradation Symposium (expected date October 2025, UK). This will present an excellent opportunity to present work to industry and academic leaders in the field of TPD. Any knowledge and innovation gained from conference would be applied to current project and shared with colleagues. Attending the conference will also be an excellent opportunity for collaboration with other researchers and industry workers.
Dr Liddle’s research goal is to establish a medicinal chemistry team in New Zealand that focuses on early-phase antimicrobial drug discovery.