Building understanding of drug entry into gram negative bacterial

There is a very clear need for new antibacterial drug treatments to combat the ever increasing problem of drug resistance. However, one of the major issues with developing new drugs for treating Gram negative bacteria is the challenge of obtaining sufficient levels of compound within the bacteria. This is due to two factors: the lack of permeability of the cell envelope and the presence of efflux pumps which remove compounds from cells.

The aims of the project will be to:

Develop a robust high throughput method for assessing intracellular unbound
concentration of drug in gram negative bacteria.

Screen chemically diverse compound libraries against the Gram negative ESKAPE pathogens (Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae) and use the data to define the key compound properties needed for drug entry into different pathogens. Predictive in silico models will then be developed and applied to drug discovery efforts to help to design potential antibacterial compounds which can enter into bacterial cells without being pumped out.
Screen compound libraries put together based on poor intracellular penetration in (2) against gram negative ESKAPE pathogen mutants where individual or multiple efflux pumps have been removed in order to develop structure activity relationships around these bacterial specific transporters and refine in silico rules linked to passive permeability of the cell envelope.

Outputs: Delivery of a more robust method for measuring intracellular unbound drug concentration than presented in current literature. Understanding which chemical features are important for compound uptake in individual bacterial species and which chemical features lead to compounds being pumped out of bacterial cells. In silico models developed for application in drug discovery programmes.

Learning: the student will gain experience of working in a Biotech style drug discovery environment and obtain training in a large number of techniques across both analytical chemistry and microbiology.

Skillsets: The student will be required to carry out mass spectrometry method development on differing instrument types (Waters Xevo TQs UPLCMSMS; Rapidfire MS), biological assay development, and a variety of techniques within microbiology. This would ideally suit someone who has a background in analytical chemistry and either experience or interest in microbiology.