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Combating antimicrobial resistance: does lipid remodelling play a role in antimicrobial resistance?

Principal Supervisor: Dr Yin Chen, School of Life Sciences

Co-supervisor: Prof David Scanlan, School of Life Sciences

PhD project title: Combating antimicrobial resistance: does lipid remodelling play a role in antimicrobial resistance?

University of Registration: University of Warwick

Project outline:

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 pathogens 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). This PlcP-mediated pathway is present in many clinically important pathogens such as Enterobacter spp. Pseudomonas spp. and members of the Burkholderia cepacia complex. Using cutting-edge lipidomics, transcriptomics and proteomics approaches, this project aims to determine the link between antimicrobial resistance and lipid remodelling using the aforementioned pathogens as model organisms.

References:

  1. Blair JM, et al 2015 Molecular mechanisms of antimicrobial resistance. Nature Reviews Microbiology 13:42-51.
  2. Sebastian et al 2016 Lipid remodelling is a widespread strategy in marine heterotrophic bacteria upon phosphorus deficiency. ISME J 10 (4), 968-978.
  3. Nikaido H 2003 Molecular basis of bacterial outer membrane permeability revisited. Microbiology and Molecular biology Reviews 67(4)593-656.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Cutting edge ‘omics tool sets and associated bioinformatics, including lipidomics, transcriptomics and proteomics
  • Molecular genetics and targeted mutagenesis
  • Analytic 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: Dr Yin Chen, University of Warwick