Dr Ian Liddle
Development of PROTAC-antibiotics to mediate targeted protein degredation in drug resistant bacteria
Project Summary
Dr Ian Liddle’s research focuses 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 Chimera (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 a new paradigm for antibiotic drug discovery.
Dr Liddle 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, he 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.
12 Month Project Update
During the Medicines New Zealand project timeline, Dr Liddle successfully synthesised new antimicrobial compounds. The new antimicrobials function as bacterial PROTACs (Proteolysis Targeting Chimeras) that can facilitate TPD of the essential bacterial protein DNA gyrase mediated by the ClpXP protease.
The new compounds were tested against pathogenic bacteria (Pseudomonas aeruginosa) and displayed antimicrobial activity. Future work will show whether the bacterial PROTACs function specifically via a TPD mechanism of action.
The results from Dr Liddle's project will support future funding applications to develop antimicrobial drugs.
In December 2025, Dr Liddle attended The International Chemical Congress of Pacific Basin Societies (Pacifichem). Pacifichem is a multiday, chemistry conference every five years in Honolulu, Hawaii. The theme for the 2025 Pacifichem conference was ‘building communities to address global challenges’.
The congress was an excellent opportunity for Dr Liddle to showcase his research conducted at the University of Otago. He presented at two separate symposia that focused on organic & medicinal chemistry, drug discovery and developing anti-infective medicines. He presented a poster (pictured) on his Innovation Jump Start Award winning project: Targeted protein degradation using degron proteolysis targeting chimeras (PROTACs) as an antimicrobial strategy against drug resistance.
Dr Liddle also presented an oral presentation on his Maurice Wilkins Centre postdoctoral work, titled: A trojan horse strategy using peptide antibiotic conjugates to overcome efflux mediated multidrug resistance in Pseudomonas aeruginosa.
Dr Liddle was accompanied by two colleagues from the Gamble lab group (University of Otago), Sushant Aryal and Julia Constantino Camilli, who also gave oral presentations from their own work at the symposia: Making Smart Drugs Smarter through Bioorthogonal Chemistry.
Dr Liddle has now relocated to Scotland to undertake post-doctoral study at the University of Edinburgh.
Dr Liddle with his Pacifichem poster.