Skip to main content

PhD project title

New tools for new antibiotic targets The development of novel probes for mechanistic studies on bacterial glycolipid-processing enzymes

Outline description, including interdisciplinary, intersectoral and international dimensions (300 words max)

Antibacterial resistance is a major threat to human health. The recent COVID-19 pandemic has highlighted the problem posed by bacterial infections, with a major study showing that half of COVID-19 fatalities were due to a secondary bacterial infection (Lancet 2020, 395, 1054). Therefore, there is a pertinent need for new antimicrobial targets.  Bacteria produce several glycopolymers and glycoproteins that are vital to their survival, including peptidoglycan, which is a key component of the bacterial cell wall. Peptidoglycan biosynthesis involves several glycolipid intermediates, all of which are linked to the cell membrane by the universal lipid carrier, undecaprenyl phosphate. The enzymes that process undecaprenyl-linked biomolecules are hot antibiotic targets, as they are vital and unique to bacteria. However, detailed studies on these enzymes have been limited due to the lack of suitable probes to interrogate their mechanism. An understanding of enzyme mechanism is a vital pre-requisite to the rationale design of inhibitors. This project aims to develop new labelled analogues of undecaprenyl phosphate as probes to perform mechanistic studies on several important enzymes, including enzymes involved in protein O-glycosylation in Burkholderia, a Gram-negative bacterium that can cause life-threatening illnesses, and undecaprenyl pyrophosphate phosphatase (UppP), an essential enzyme in all bacteria. This is a highly interdisciplinary project. Natural product isolation, chemical synthesis of glycolipid probes and enzymatic assays will be performed in the Cochrane Lab. Protein expression, growth of protein crystals and protein/glycolipid co-crystals will be performed in the Valvano Lab (for Burkholderia enzymes) and Caffrey Lab (collaborators at TCD that work with UppP). Macromolecular X-ray crystallography will be performed under the supervision of Dr. Vincent Olieric (non-HEI partner) at the Paul Scherrer Institute. This project will increase our mechanistic understanding of bacterial glycolipid-processing enzymes and could enable the rational design of inhibitors of these enzymes, leading to new classes of antibiotics.

Key words/descriptors

 

 

Antimicrobials, enzyme mechanisms, chemical probes, macromolecular X-ray crystallography, antibiotics

 

Fit to CITI-GENS theme(s)

Life Sciences

Supervisor Information

 

 

First Supervisor: Dr Stephen Cochrane                                School: Chemistry and Chemical Engineering

Second Supervisor: Prof Miguel Valvano                            School: Wellcome-Wolfson Institute for Experimental Medicine

Third Supervisor:  Dr Vincent Olieric                                    Company: Paul Scherrer Institute

Collaborator: Prof Martin Caffrey                                         School: Biochemistry, Trinity College Dublin

Name of non-HEI partner(s)

 

The Paul Scherrer Institute, Switzerland

 

Contribution of non-HEI partner(s) to the project:

 

 

 

Will provide all training and supervision required for acquiring X-ray crystal data at the state-of-the-art Swiss Light Source, as well as cover costs associated with performing these experiments. This is an international centre of excellence so ample opportunities will also be available to the PhD student to network with scientists from all over the world.

 

 

. Please describe the profile of the non-HEI partner and the nature of the relationship.    

 

 

The Paul Scherrer Institute (PSI) develops, builds and operates large, complex research facilities and makes them available to the national and international research community. The institute's own key research priorities are in the fields of matter and materials, energy and environment and human health. PSI is committed to the training of future generations. Altogether PSI employs 2100 people, of which about one quarter are post-docs, post-graduates or apprentices, thus being the largest research institute in Switzerland. PSI is part of the ETH Domain.

Macromolecular Crystallography at the Swiss Light Source (SLS) group operates two high performance undulator beam lines as well as a state-of-the-art bending magnet beamline for protein crystallography. The group is involved in several aspects of protein crystallography including the development of advanced beamline instrumentation and crystallographic methods, as well as structural biology projects. Dr Vincent Olieric is the beamline scientist in the Laboratory for Macromolecules and Bioimaging (LSB) at the SLS. His expertise includes structural biology, macromolecular crystallography, crystallographic data collection strategies and synchrotron beamlines instrumentation.

It is envisaged that the PSI will support with the Doctoral Programme in the following ways: 1) host the PhD student at various points throughout the project for acquisition of X-ray crystal data; 2) provide all necessary supervision, mentoring and training required; 3) offer additional training courses at the PSI for personal development and 4) cover the consumables costs associated with the research activities undertaken by the PhD student during their time at the PSI and provide access to necessary laboratory equipment and infrastructure.

Dr Cochrane and Prof Caffrey, a collaborator on this project, already collaborate with Dr Olieric on X-ray methods for macromolecular crystallographic data collection so a strong relationship is in place.

Subject area

Chemical Biology