Lipid remodelling in host-pathogen interaction and antimicrobial resistance

Programme overview:
This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice.

Project:
Antimicrobial resistance (AMR) describes the ability of microbes to negate the effects of the drugs used to treat them. This includes the resistance of bacteria to antibiotics, within which individual bacterial species are becoming resistant to multiple different classes of antibiotics. One such multi-drug resistant species is Pseudomonas aeruginosa (P. aeruginosa); a bacterial species that often presents concomitantly with other existing illnesses, for example in cystic fibrosis or burns patients. P. aeruginosa is particularly problematic due to its naturally low susceptibility to antibiotics, whereas other bacterial species need to acquire their mechanisms for antibiotic resistance.

Bacterial cells have an outer membrane, composed of lipids (fats), that is their first barrier to antibiotic attack. The membrane often contains resistance mechanisms, such as proteins to pump the drug back out of the cell, or to break it down. Importantly, bacteria also have the ability to change the types of lipids that make up the outer membrane. This results in changes to the permeability and selectivity of the membrane, with the possibility that this affects the ability of the drug to enter the bacterial cell. The aim of this project is to establish the link between antimicrobial resistance and the changes in membrane lipid composition.

To investigate this hypothesis, first it will be confirmed that P. aeruginosa is able to modify the lipids in its membrane in response to clinically relevant environments. Subsequently, various different classes of antimicrobials will be tested after the bacteria has modified its lipid membrane, to see if this alters their ability to kill the bacterium. Finally, the project will investigate how the changes to the bacterial membrane lipids affect its ability to interact with the target host, through using both a species of worm (nematode) frequently used in scientific research, Caenorhabditis elegans, and also laboratory cultured human cells.