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Low-dose nitric oxide as targeted anti-biofilm adjunctive therapy to treat chronic Pseudomonas aeruginosa infection in cystic fibrosis

Low-dose nitric oxide as targeted anti-biofilm adjunctive therapy to treat chronic Pseudomonas aeruginosa infection in cystic fibrosis
Low-dose nitric oxide as targeted anti-biofilm adjunctive therapy to treat chronic Pseudomonas aeruginosa infection in cystic fibrosis
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.
1525-0016
2104-2116
Howlin, Robert P.
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Cathie, Katrina
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Hall-Stoodley, Luanne
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Cornelius, Victoria
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Duignan, Caroline
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Allan, Raymond N.
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Fernandez, Bernadette O.
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Barraud, Nicolas
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Bruce, Ken D.
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Jefferies, Johanna
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Kelso, Michael
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Kjelleberg, Staffan
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Rice, Scott A.
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Rogers, Geraint B.
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Pink, Sandra
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Smith, Caroline
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Sukhtankar, Priya S.
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Salib, Rami
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Legg, Julian
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Carroll, Mary
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Daniels, Thomas
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Feelisch, Martin
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Stoodley, Paul
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Clarke, Stuart C.
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Connett, Gary
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Faust, Saul N.
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Webb, Jeremy S.
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Howlin, Robert P.
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Cathie, Katrina
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Hall-Stoodley, Luanne
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Cornelius, Victoria
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Duignan, Caroline
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Allan, Raymond N.
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Fernandez, Bernadette O.
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Barraud, Nicolas
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Bruce, Ken D.
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Jefferies, Johanna
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Kelso, Michael
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Kjelleberg, Staffan
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Rice, Scott A.
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Rogers, Geraint B.
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Pink, Sandra
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Smith, Caroline
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Sukhtankar, Priya S.
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Salib, Rami
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Legg, Julian
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Carroll, Mary
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Daniels, Thomas
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Feelisch, Martin
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Stoodley, Paul
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Clarke, Stuart C.
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Connett, Gary
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Faust, Saul N.
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Webb, Jeremy S.
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Howlin, Robert P., Cathie, Katrina, Hall-Stoodley, Luanne, Cornelius, Victoria, Duignan, Caroline, Allan, Raymond N., Fernandez, Bernadette O., Barraud, Nicolas, Bruce, Ken D., Jefferies, Johanna, Kelso, Michael, Kjelleberg, Staffan, Rice, Scott A., Rogers, Geraint B., Pink, Sandra, Smith, Caroline, Sukhtankar, Priya S., Salib, Rami, Legg, Julian, Carroll, Mary, Daniels, Thomas, Feelisch, Martin, Stoodley, Paul, Clarke, Stuart C., Connett, Gary, Faust, Saul N. and Webb, Jeremy 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. (doi:10.1016/j.ymthe.2017.06.021).

Record type: Article

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.

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Accepted/In Press date: 24 June 2017
e-pub ahead of print date: 24 July 2017
Published date: 6 September 2017

Identifiers

Local EPrints ID: 421281
URI: http://eprints.soton.ac.uk/id/eprint/421281
ISSN: 1525-0016
PURE UUID: 78a47ee5-d893-4e67-8869-b2d254662ffa
ORCID for Bernadette O. Fernandez: ORCID iD orcid.org/0000-0001-6337-0381
ORCID for Rami Salib: ORCID iD orcid.org/0000-0002-6753-7844
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158
ORCID for Paul Stoodley: ORCID iD orcid.org/0000-0001-6069-273X
ORCID for Stuart C. Clarke: ORCID iD orcid.org/0000-0002-7009-1548
ORCID for Gary Connett: ORCID iD orcid.org/0000-0003-1310-3239
ORCID for Saul N. Faust: ORCID iD orcid.org/0000-0003-3410-7642
ORCID for Jeremy S. Webb: ORCID iD orcid.org/0000-0003-2068-8589

Catalogue record

Date deposited: 31 May 2018 16:30
Last modified: 16 Mar 2024 06:42

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Contributors

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

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