Lipid remodelling: does it play a role in antibiotic resistance?

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences


In the 21st century, antimicrobial resistance has become a serious threat to global public health. Resistant microbes are able to survive routine medical treatment, resulting in persistent infections. New resistance mechanisms are constantly emerging and it is vital to understand how these mechanisms work. In this project, the lipid membrane bilayer is under investigation, which is the first barrier of defence against antimicrobials. A possible mechanism of antimicrobial resistance is the remodelling of membrane lipids. Bacteria remodel their membrane lipid composition in response to changing environmental stimuli, such as nutrient availability. It is hypothesised that lipid remodelling could result in changes to antibiotic trafficking, possibly due to modifications in the protein composition. Opportunistic bacterial pathogens such as Pseudomonas spp. and members of the Burkholderia cepacia complex are highly resistant and contain the main phospholipase enzyme required for lipid remodelling. Using these model organisms, the link between antimicrobial resistance and lipid remodelling will be investigated.


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Description So far, we have discovered that the PlcP enzyme is involved in lipid remodeling in Burkholderia cenocepacia. Under phosphate limiting conditions, wild-type B. cenocepacia generates glycolipids, whereas the plcP deletion mutant can no longer produce these glycolipids. In turn, we have also identified membrane lipids that have not been described in Burkholderia species before. We have shown that using a Galleria mellonella infection model, the PlcP deletion mutant is significantly less virulent than the wild-type. When assessing the intracellular survival, the survival of PlcP deletion mutant was 3-log less than that of the wild-type. These results suggest lipid remodeling is either directly or indirectly involved in virulence for B. cenocepacia. We also have a large dataset for proteomic changes between the wild-type in a high and low phosphate condition which will give us insights into which processes are differentially regulated by the PhoBR two-component system in response to phosphate limitation.
Exploitation Route There are many pathways in which this research can be taken forward. Primarily, my supervisor Dr Yin Chen is seeking BBSRC funding to fund a collaborative project between our colleagues at Queens University Belfast to investigate further the phosphate starvation response within macrophages and how they may be limiting phosphate availability to infecting pathogens. Another major research pathway my supervisor would like to investigate is finding inhibitors for the PlcP enzyme which may help with drug development against these deadly pathogens.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology,Other

Description Burkholderia mutants and Galleria 
Organisation Queen's University Belfast
Country United Kingdom 
Sector Academic/University 
PI Contribution Lipid LC/MS analysis for various Burkholderia samples
Collaborator Contribution 2-week host of Holly Shropshire for training on using the Galleria infection model Provided 4 types of plasmids for mutagenesis of Burkholderia
Impact Possible grant between the two groups for further research in phosphate starvation in macrophages and Burkholderia.
Start Year 2018