Principal Supervisor: Professor Yin Chen
Co-supervisor: Professor Ioannis Nezis
PhD project title: Uncovering the role of lipid renovation in bacteria-host interactions
University of Registration: University of Warwick
Antimicrobial resistance is one of the most serious threats to humans in the 21st century. Hence, understanding antimicrobial resistance mechanisms is pivotal for combating superbugs that are constantly emerging.
Pathogens use many strategies to combat challenges by antimicrobial compounds in order to better adapt or survive antibiotic insults. These include the induction of efflux pumps or the synthesis of enzymes involved in degrading or modifying antibiotics (e.g. β-lactamases) (Blair et al 2015).
This project aims to determine whether there is another, previously overlooked, dimension to antimicrobial resistance mechanisms, namely the remodelling of membrane lipids. Lipid remodelling is a process whereby bacteria selectively modify their membrane lipid composition in response to a particular environmental stimulus, e.g. the availability of a specific nutrient (see Sebastian et al 2016). Such remodelling potentially plays a role in dictating the permeability and selectivity of the outer membrane, hence mediating antimicrobial resistance. After all, from a pathogen’s perspective, the membrane lipid bilayer forms the first-line of defence against the invasion of an antibiotic (Nikaido 2003). We hypothesize that changes in membrane lipid composition will result in selective recruitment of outer membrane proteins (such as efflux pumps, porins etc), therefore affecting antibiotic trafficking through the membrane. We have recently discovered the central pathway responsible for bacterial lipid remodelling, involving an unusual intracellular phospholipase (PlcP) and demonstrated that lipid remodelling is a common adaptation strategy for a diverse range of bacteria (Sebastian et al., 2016; Jones et al., 2021). This PlcP-mediated pathway is present in many clinically important pathogens such as Pseudomonas aeruginosa and Burkholderia cenocepacia. Interesting, this PlcP-mediated pathway is also essential for intracellular survival and plays a key role in subverting host autophagy and the innate immunity response, thus contributing to the success and spread of these PlcP-containing pathogens during infection. Using cutting-edge omics (lipidomics, transcriptomics and proteomics), advanced imaging (confocal) and cellular biology approaches (macrophages, autophagy biomarkers), this project aims to determine the link between lipid remodelling and antimicrobial resistance and intracellular survival using P. aeruginosa and B. cenocepacia as model organisms.
BBSRC Strategic Research Priority: Understanding the Rules of Life - Microbiology
Techniques that will be undertaken during the project:
- Cutting edge ‘omics tool sets and associated bioinformatics, including lipidomics, transcriptomics and dual-proteomics
- Molecular genetics and targeted mutagenesis
- Trainings on Infection models, insects/ cell cultures
- Analytical skills including HPLC, ion-exchange chromatography and gas chromatography
- Biochemical skills, including membrane protein isolation and purification and mass spectrometry
- Health and safety training and handling of class-2 human pathogens
Contact: Professor Yin Chen