Format

Send to

Choose Destination
Mol Ther. 2017 Sep 6;25(9):2104-2116. doi: 10.1016/j.ymthe.2017.06.021. Epub 2017 Jul 24.

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

Author information

1
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; University Hospital Southampton NHS Foundation Trust, Southampton SO16, 6YD, UK; Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK.
2
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; University Hospital Southampton NHS Foundation Trust, Southampton SO16, 6YD, UK; Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
3
Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH 43210-2210, USA; Southampton NIHR Wellcome Trust Clinical Research Facility, Southampton SO16 6YD, UK.
4
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; Imperial College London School of Public Health, London SW7 2AZ, UK.
5
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; University Hospital Southampton NHS Foundation Trust, Southampton SO16, 6YD, UK; Centre for Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK.
6
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; University Hospital Southampton NHS Foundation Trust, Southampton SO16, 6YD, UK; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK; Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton SO17 1BJ, UK; Southampton NIHR Wellcome Trust Clinical Research Facility, Southampton SO16 6YD, UK.
7
Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
8
Centre for Marine Bio-Innovation and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
9
Kings College London Institute of Pharmaceutical Science, London WC2R 2LS, UK.
10
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; University Hospital Southampton NHS Foundation Trust, Southampton SO16, 6YD, UK; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK; Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton SO17 1BJ, UK; Public Health England, Southampton SO17 1BJ, UK.
11
Illawarra Health and Medical Research Institute and School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.
12
Centre for Marine Bio-Innovation and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia; Singapore Centre on Environmental Life Sciences Engineering and Nanyang Technological University, School of Biological Sciences, Singapore 637551, Singapore.
13
Kings College London Institute of Pharmaceutical Science, London WC2R 2LS, UK; Infection and Immunity Theme, South Australia Health and Medical Research Institute, North Terrace, Adelaide, SA 5000, Australia; Flinders University School of Medicine, Bedford Park, Adelaide, SA 5042, Australia.
14
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; University Hospital Southampton NHS Foundation Trust, Southampton SO16, 6YD, UK.
15
Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton SO17 1BJ, UK; Southampton NIHR Wellcome Trust Clinical Research Facility, Southampton SO16 6YD, UK.
16
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; University Hospital Southampton NHS Foundation Trust, Southampton SO16, 6YD, UK; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK; Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
17
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; University Hospital Southampton NHS Foundation Trust, Southampton SO16, 6YD, UK; Microbial Infection and Immunity, The Ohio State University College of Medicine, Columbus, OH 43210-2210, USA; National Centre for Advanced Tribology at Southampton, Faculty of Engineering, University of Southampton, Southampton SO17 1BJ, UK.
18
NIHR Southampton Respiratory Biomedical Research Centre, Southampton SO16 6YD, UK; University Hospital Southampton NHS Foundation Trust, Southampton SO16, 6YD, UK; Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, UK; Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton SO17 1BJ, UK; Southampton NIHR Wellcome Trust Clinical Research Facility, Southampton SO16 6YD, UK. Electronic address: s.faust@soton.ac.uk.

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.

KEYWORDS:

Pseudomonas aeruginosa; cystic fibrosis; nitric oxide

PMID:
28750737
PMCID:
PMC5589160
DOI:
10.1016/j.ymthe.2017.06.021
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center