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

Robert P Howlin, Katrina Cathie, Luanne Hall-Stoodley, Victoria Cornelius, Caroline Duignan, Raymond N Allan, Bernadette O Fernandez, Nicolas Barraud, Ken D Bruce, Johanna Jefferies, Michael Kelso, Staffan Kjelleberg, Scott A Rice, Geraint B Rogers, Sandra Pink, Caroline Smith, Priya S Sukhtankar, Rami Salib, Julian Legg, Mary CarrollThomas Daniels, Martin Feelisch, Paul Stoodley, Stuart C Clarke, Gary Connett, Saul N Faust, Jeremy S Webb

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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.

Original languageEnglish
Pages (from-to)2104-2116
Number of pages13
JournalMOLECULAR THERAPY
Volume25
Issue number9
DOIs
Publication statusPublished - Sep 2017

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Keywords

  • Pseudomonas aeruginosa
  • cystic fibrosis
  • nitric oxide

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  • Cite this

    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., Kjelleberg, S., Rice, S. A., Rogers, G. B., Pink, S., Smith, C., Sukhtankar, P. S., Salib, R., Legg, J., ... Webb, J. S. (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. https://doi.org/10.1016/j.ymthe.2017.06.021