The University of Southampton
University of Southampton Institutional Repository

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.
f3c84990-6196-47d4-ad8a-80954ea46c7f
Cathie, Katrina
ec8dd2eb-0be9-4567-b87d-72eadf5a254b
Hall-Stoodley, Luanne
94ebdc00-b549-4488-b15f-5310fb965f5b
Cornelius, Victoria
b75c21d7-2c25-495c-9107-e39453a72bdd
Duignan, Caroline
48bd5ba4-ef7a-4ac0-8c46-faeaa47f2792
Allan, Raymond N.
390a7d0a-38e1-410a-8dfe-c8ef8408f5e1
Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Barraud, Nicolas
01e480a6-d225-44eb-acde-433c5b24bb82
Bruce, Ken D.
e4f5f6c6-3041-4c04-9e73-11d2d76c1d2a
Jefferies, Johanna
9468e292-0b41-412d-9470-944e257c7bcf
Kelso, Michael
6afd2b75-c893-44cf-8b86-93e89e21f894
Kjelleberg, Staffan
043b66b5-130c-42f2-99b3-ec3eecf3248e
Rice, Scott A.
4f9516db-1d35-4211-878c-bb6cfb2a6b4a
Rogers, Geraint B.
bd90d82a-4150-4e01-a755-b81559586da2
Pink, Sandra
b4278a95-9a1e-4693-9a7a-12f596acfbcc
Smith, Caroline
c53cf3b5-c529-48a9-aa7a-f983b28c8ce8
Sukhtankar, Priya S.
8f1be4ff-2b8e-461c-9997-5983b75477ab
Salib, Rami
d6fde1c1-5b5e-43f7-ae1c-42cce6a0c9fc
Legg, Julian
72afc985-52a4-4504-84c4-50a8e018891f
Carroll, Mary
b836d262-6b07-4006-9c81-26653a26588b
Daniels, Thomas
9a8ab6f0-2eb9-4703-b536-f86923888213
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Stoodley, Paul
08614665-92a9-4466-806e-20c6daeb483f
Clarke, Stuart C.
f7d7f7a2-4b1f-4b36-883a-0f967e73fb17
Connett, Gary
55d5676c-90d8-46bf-a508-62eded276516
Faust, Saul N.
f97df780-9f9b-418e-b349-7adf63e150c1
Webb, Jeremy S.
ec0a5c4e-86cc-4ae9-b390-7298f5d65f8d
Howlin, Robert P.
f3c84990-6196-47d4-ad8a-80954ea46c7f
Cathie, Katrina
ec8dd2eb-0be9-4567-b87d-72eadf5a254b
Hall-Stoodley, Luanne
94ebdc00-b549-4488-b15f-5310fb965f5b
Cornelius, Victoria
b75c21d7-2c25-495c-9107-e39453a72bdd
Duignan, Caroline
48bd5ba4-ef7a-4ac0-8c46-faeaa47f2792
Allan, Raymond N.
390a7d0a-38e1-410a-8dfe-c8ef8408f5e1
Fernandez, Bernadette O.
9890aabc-1fe6-4530-a51e-31182e537131
Barraud, Nicolas
01e480a6-d225-44eb-acde-433c5b24bb82
Bruce, Ken D.
e4f5f6c6-3041-4c04-9e73-11d2d76c1d2a
Jefferies, Johanna
9468e292-0b41-412d-9470-944e257c7bcf
Kelso, Michael
6afd2b75-c893-44cf-8b86-93e89e21f894
Kjelleberg, Staffan
043b66b5-130c-42f2-99b3-ec3eecf3248e
Rice, Scott A.
4f9516db-1d35-4211-878c-bb6cfb2a6b4a
Rogers, Geraint B.
bd90d82a-4150-4e01-a755-b81559586da2
Pink, Sandra
b4278a95-9a1e-4693-9a7a-12f596acfbcc
Smith, Caroline
c53cf3b5-c529-48a9-aa7a-f983b28c8ce8
Sukhtankar, Priya S.
8f1be4ff-2b8e-461c-9997-5983b75477ab
Salib, Rami
d6fde1c1-5b5e-43f7-ae1c-42cce6a0c9fc
Legg, Julian
72afc985-52a4-4504-84c4-50a8e018891f
Carroll, Mary
b836d262-6b07-4006-9c81-26653a26588b
Daniels, Thomas
9a8ab6f0-2eb9-4703-b536-f86923888213
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Stoodley, Paul
08614665-92a9-4466-806e-20c6daeb483f
Clarke, Stuart C.
f7d7f7a2-4b1f-4b36-883a-0f967e73fb17
Connett, Gary
55d5676c-90d8-46bf-a508-62eded276516
Faust, Saul N.
f97df780-9f9b-418e-b349-7adf63e150c1
Webb, Jeremy S.
ec0a5c4e-86cc-4ae9-b390-7298f5d65f8d

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.

Text
24454_2_merged_1498214088 for eprints under embargo - Accepted Manuscript
Download (802kB)
Text
1-s2.0-S1525001617303052-main - Version of Record
Available under License Creative Commons Attribution.
Download (3MB)

More information

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

Identifiers

Local EPrints ID: 421281
URI: https://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: 03 Dec 2019 05:22

Export record

Altmetrics

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

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×