Novel approaches in drug targeting and delivery to combat Gram-negative bacterial pathogens

A major problem with drug development is that active compounds are not always delivered to the requisite site. Rationale: A major problem with drug development is that active compounds are not always delivered to the requisite site. This project seeks to span the disciplines of microbiology and bioengineering to develop new technologies to target Gram-negative bacterial pathogens, one of the most serious health threats of our time. Preliminary work in the Shepherd lab has identified a class of steroid drugs that inhibit cytochrome bd, an emerging drug target, from E. coli and Staphylococcus aureus (Henry et al. 2023), and has very recently cloned and expressed recombinant cytochrome bd complexes from a variety of Gram-negative pathogens (e.g. Burkholderia cenocepacia, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumanii). The Evans lab has extensive expertise in a range of drug formulation techniques, recently including the use of polymersomes to deliver antimicrobials to host macrophages to kill intracellular bacteria (Porges et al. 2021). Approaches and preliminary work: The student will quantify the efficacy of steroid drugs against cytochrome bd from a range of Gram-negative pathogens using oxygen electrode measurements, viability assays, and will trial a novel high-throughput fluorescence technique to measure oxygen consumption that has been recently developed in the host lab. Novel nanoencapsulation techniques will be developed to optimise steroid drug loading and access to the aforementioned bacterial pathogens that have been internalised by immune cells. Potential Impact: This work will develop cutting edge research technologies that could be relevant to a number of different antimicrobial classes, and could change the way that drug susceptibility work is undertaken with immune cells and intracellular pathogens.