Biophysical and Biochemical Approaches to Measure Compound Permeation Across the Gram-negative Cell Wall

This project is offered as part of the Medical Research Foundation National PhD Training Programme in AMR: https://www.findaphd.com/search/PhDDetails.aspx?CAID=3755

Outer membrane (OM) penetration is an important factor which can make it difficult to develop new antibiotics to treat Enterobacteriaceae and Pseudomonas aeruginosa infections. Deeper insights into the structure-activity relationships that improve penetration will enable the development of the next generation of agents to treat these serious infections. Initially, this project will develop and validate novel (mass spectrometry based) penetration assays to extensively profile the penetration of a set of reference β-lactam compounds against isogenic and clinically relevant strains of E. coli. Once the assays are validated, they will be used to profile three different sets of mechanistically distinct and specially designed series of compounds against the same set of strains. In parallel, we will establish novel in vitro assays using synthetic cells walls, using the microfluidics platform available at Cambridge with Dr J Cama. This will involve the generation of increasingly complex vesicles with defined porin composition and within the core of the vesicle defined target proteins. This system once developed will provide a state of the art platform to better characterise compounds that can penetrate Gram negative bacterial cell walls. Finally, we will also use state-of-the-art high resolution single cell Raman Spectroscopic analysis with Prof S. Evans (Leeds) to further characterise compound permeation into cells. The successful candidate will be enrolled in the Medical Research Council Doctoral Training Programme at Warwick which will provide additional training opportunities and local student cohort activities.

Apply here: https://postgrad.warwick.ac.uk/SWIFT.web/skins/pgapp/login.aspx

As part of your application, you need to Identify that the School of Life Sciences will be your primary host but linked to the MRC DTP (WMS) https://warwick.ac.uk/fac/med/study/mrcdtp/apply/ and funded by Medical Research Foundation National PhD Training Programme in AMR Research. Additionally, under the ‘Research Details’ section, please indicate that you are applying for a Medical Research Foundation National PhD Training Programme in AMR Research funded project and give the project title and names of the supervisors. For any queries, please contact [Email Address Removed] or [Email Address Removed]