Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis

Authors

Robert P. Howlin, University of Southampton, NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton
Katrina Cathie, NIHR Southampton Respiratory Biomedical Research Centre, University of Southampton, University Hospital Southampton
Luanne Hall-Stoodley, Ohio State University, Wellcome Trust Clinical Research Facility
Victoria Cornelius, NIHR Southampton Respiratory Biomedical Research Centre, Imperial College London
Caroline Duignan, University of Southampton, University Hospital Southampton, NIHR Southampton Respiratory Biomedical Research Centre
Raymond Allan, University Hospital Southampton, University of Southampton, Wellcome Trust Clinical Research Facility, NIHR Southampton Respiratory Biomedical Research Centre
Bernadette Fernandez, University of Southampton
Nicolas Barraud, University of New South Wales
Ken Bruce, King's College London
Johanna Jefferies, NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, University of Southampton, Public Health England
Michael J. Kelso, University of WollongongFollow

RIS ID

115557

Publication Details

Howlin, R. P., Cathie, K., Hall-Stoodley, L., Cornelius, V., Duignan, C., Allan, R. N., Fernandez, B. O., Barraud, N., Bruce, K. D., Jefferies, J., Kelso, M. et al (2017). Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis. Molecular Therapy, 25 (9), 2104-2116.

Abstract

Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases.