Bacterial biofilms represent a significant challenge to medicine due to their recalcitrance to antibiotics. This project adopts a multidisciplinary approach to implementing low dose nitric oxide to disrupt biofilms and improve antibiotic sensitivity in cystic fibrosis.
Bacteria commonly exist in either a free-living or “planktonic” state or in matrix-enclosed microcolonies known as biofilms. Bacterial biofilms present a major challenge in medicine due to their recalcitrance towards antimicrobials, relative to the same bacteria in a planktonic state. In CF, patient lungs become colonised with bacteria and a particularly poor prognostic indicator is the identification of the opportunistic pathogen
Pseudomonas
aeruginosa
.
Despite aggressive antibiotic regimes to eradicate or control bacterial infection, chronic and persistent colonisation often occurs leading to cardiorespiratory failure and death. It is thought that bacterial biofilms act as a reservoir for infection, seeding infection throughout the lung.
The aim of the project is to evaluate nitric oxide (NO) as a novel therapy for cystic fibrosis. Through interaction with phosphodiesterases resulting in decreased cyclic di-GMP concentrations, low dose nitric oxide is capable of inducing dispersal of Pseudomonas biofilms into a planktonic state. Our hypothesis is that delivery of low dose NO to the CF lung will reduce carriage of
P.
aeruginosa
significantly by inducing biofilm dispersal, therefore subverting antibiotic resistance mechanisms associated with biofilm structure and increasing bacterial antibiotic sensitivity.
Laboratory work on the project is evaluating nitric oxide as a potential therapy, both in in vitro and ex vivo studies using a variety of cell-based, microscopy and molecular techniques. Using nitric oxide donors, we are assessing the response of
P. aeruginosa
and multispecies biofilms to NO, both in terms of dispersal kinetics and antibiotic sensitivity, as well as the reaction to NO-mediated dispersal at a cellular level. Moreover, laboratory work is providing the fundamental information required to begin a phase 2 pilot study to discover whether non-toxic levels of NO administered to patients during an episode of acute infection (exacerbation) will increase the effectiveness of antibiotic therapy.
Funding:
Respiratory Biomedical Research Unit, Southampton General Hospital
Funding duration:
2008 - 2011