Inhibition of a protein-protein interaction mediating antibiotic resistance

The dramatic rise in antibiotic resistance is threatening our ability to treat bacterial infections and precipitating a public health crisis. The Chief Medical Officer for England has warned that antibiotic resistance poses a ‘catastrophic threat’ on a par with climate change and terrorism. Indeed, antimicrobial resistance is predicted to overtake cancer as a cause of death by 2050. With few new drugs in development to treat these infections an alternative strategy is to develop adjuvants that can be administered with an antibiotic and can disrupt existing resistance mechanisms to extend the usefulness of existing antibiotics.

Fusidic acid (FA) is one of the few remaining oral antibiotics that is active against MRSA but resistance is rising rapidly due to expression of the FusB family of proteins. FA binds to Elongation Factor G (EF-G) while it is bound to the ribosome during protein synthesis and prevents its release, halting protein synthesis. However FusB bind to EF-G in these stalled complexes and promotes dissociation so protein synthesis can continue. Protein-protein interactions (PPIs) such as that between EF-G and FusB have not previously been targeted in preventing antibiotic resistance due to difficulty in developing PPI inhibitors. However, new tools and recent successes in inhibiting PPIs suggests these should now be revisited. Prior to a drug discovery campaign, however, it is necessary to identify and validate a region of the PPI interface that has the potential to be inhibited by a small molecule. This project aims to identify such a region in the EF-G:FusB PPI interface to establish how to disrupt the EF-G:FusB interaction and therefore inhibit resistance to FA.

The PhD student will work as part of a multidisciplinary collaboration between the School of Molecular and Cellular Biology and the School of Chemistry, spending time working in both areas, to identify a possible druggable site to inhibit the PPI. They will use a combination of mutagenesis, structural biology techniques, biochemical and biophysical assays and chemical synthesis of peptides to identify modified peptides that can prevent EF-G:FusB binding and which have enhanced physiochemical properties. They will receive training in protein expression and purification, molecular biology techniques, solid-phase peptide synthesis, biophysical techniques and structural biology techniques such as NMR spectroscopy and X-ray crystallography.

This studentship is available from October 2019. Applications are invited from motivated students interested in multidisciplinary research and close on 1st May 2019. Please contact Dr Jennifer Tomlinson ([Email Address Removed]) for further details about this opportunity.