Chronic Pseudomonas aeruginosa biofilm infections pose a significant problem in cystic fibrosis patients, with increased tolerance to current clinical antimicrobial therapies. This project will explore new approaches to combat biofilm infections using novel nitric oxide releasing prodrugs to induce biofilm dispersal.
Bacteria commonly exist in communities enclosed within a self-produced matrix known as biofilms. Biofilms, in particular those formed by the bacterium Pseudomonas aeruginosa (PA), are key to cystic fibrosis (CF) pathogenesis. Chronic PA infections in CF patients are often linked with increased morbidity and mortality.
In the biofilm state, bacteria display an elevated recalcitrance to antibiotics and render conventional therapeutic regimes poorly effective. Consequently, there remains a vital need for new and improved treatments that address the issue of biofilm bacteria, to further improve survival rates and patient quality of life.
This project will explore the efficacy of a novel series of dispersal-inducing nitric oxide (NO)-releasing prodrugs, that release NO in the presence of bacterial beta-lactamases, are effective in dispersing PA biofilms in-vitro, and potentiate the action of antibiotics within the CF lung.
For the application of these therapeutics, the role that the biofilm plays within CF lung disease needs to be addressed. To better understand the interactions between biofilm and antimicrobials during therapy, this project will investigate the morphology of biofilms during the differing stages in the management of pulmonary exacerbations in CF patients. A better understanding of the behaviour of P aeruginosa biofilms in the CF lung may guide personalised therapeutic approaches.
The project will focus on key challenges that must be addressed for further preclinical development of these compounds and will employ a range of microbiological based molecular and microscopy techniques including 3D confocal laser scanning microscopy (CLSM) in combination with fluorescence in-situ hybridisation (FISH).
Image: Direct 3D CLSM FISH imaging of P. aeuginosa biofilm aggregates in CF patient sputum
Supervisors:
Professor Jeremy Webb
Professor Saul Faust
Professor Gary Connett
PGR student: Declan Power
Funding provider:
NIHR Southampton Biomedical Research Centre
Cystic Fibrosis Trust via the Imperial College London-led Strategic Research Centre (SRC)
Funding dates: September 2019- September 2022