Antibiotic resistance is projected to cause 10 million deaths per year by 2050, with gram-negative (diderm) pathogens comprising 9 of the 12 bacteria that pose the greatest threat to human health (World Health Organisation). These pathogens have a unique outer membrane (OM) that acts as a first line of defence against an assault from potentially harmful molecules to the bacteria, such as antibiotics. Finding ways to prevent correct assembly of the OM may therefore produce new routes to kill gram-negative bacteria, or make them more susceptible to existing antibiotics.
Recently, we have been studying the mechanism by which beta-barrel outer membrane proteins (OMPs) reach the OM, how chaperones facilitate OMP delivery across the periplasm, and how the β-barrel assembly machinery (BAM) folds/inserts its clients into the OM, yielding new insights into the mechanism of OM assembly (e.g. Schiffrin et al, Commun Biol, 2022; White et al., Nat Commun, 2021; Calabrese et al, Nat Commun, 2020).
In this project we aim to gain new information about a key player in OMP assembly, the periplasmic chaperone SurA. This work builds on our previous studies, in which we have identified two key hotspot regions on SurA that are critical for OMP recognition and we are looking for a new team member to help us address the following important questions, using biochemical and biophysical tools:
• What are the sequence determinants for OMP recognition at the hotspot regions we have already identified?
• How does SurA modulate the conformational ensemble of its different OMP clients and remodel them to ensure they remain folding-competent and ready for delivery to BAM?
• How do mutations in key hotspots alter the range of OMPs found in the OM and are different hotspots on SurA responsible for binding different OMPs?
• Can we target the OMP binding hotspots on SurA as a route to new antibacterials?
Given that deletion of SurA results in OM defects, including impaired virulence factor assembly, reduced pathogenicity, induction of cell envelope stress responses, and loss of OM integrity (heightened sensitivity to antibiotics), SurA could be a good target for the development of new antimicrobial agents. However, this is hampered by a lack of mechanistic knowledge about SurA function. This project aims to address this gap in our understanding, by combining cutting edge biophysical, structural, and biochemical approaches to target this fascinating chaperone machinery.
You will be based in the laboratories of Dr Antonio Calabrese, Prof Sheena Radford and Dr Anastasia Zhurvaleva, and work closely with collaborators within the Astbury Centre at Leeds. In order to answer these vital questions we will apply integrative structural biology methods, giving you an opportunity to enhance you skills and to learn different methods to study biological mechanisms in our collaborative and supportive team. You should have a PhD (or be close to completion) in Chemistry, Biochemistry, Biophysics or a related discipline. You should have significant experience in protein structure/function analysis and training in any techniques that you lack experience in will be provided.
To explore the post further or for any queries you may have, please contact:
Dr Antonio Calabrese, Sir Henry Dale Fellow and University Academic Fellow
Email:
[email protected] Prof Sheena Radford, Astbury Professor of Biophysics
Email:
[email protected]Dr Anastasia Zhurvaleva, Lecturer in Biological NMR Spectroscopy
Email:
[email protected]Location: Leeds - Main Campus
Faculty/Service: Faculty of Biological Sciences
School/Institute: School of Molecular & Cellular Biology / Astbury Centre for Structural Molecular Biology
Category: Research
Grade: Grade 7
Salary: £37,099 to £44,263 p.a.
Due to funding limitations it is unlikely an appointment will be made above £40,521
Working Time: 100% FTE - We are open to discussing flexible working arrangements
Post Type: Full Time
Contract Type: Fixed Term (available for 39 months from 1st April 2024, subject to start date.)
Release Date: Thursday 08 February 2024
Closing Date: Sunday 03 March 2024
Interview Date: To be confirmed
Reference: FBSAS1073
https://jobs.leeds.ac.uk/vacancy.aspx?ref=FBSAS1073
