Macrolide treatment inhibits pseudomonas aeruginosa quorum sensing in non-cystic fibrosis bronchiectasis: An analysis from the bronchiectasis and low-dose erythromycin study trial

Lucy D. Burr, Geraint B. Rogers, Alice C H Chen, Brett R. Hamilton, Gertruida F. Pool, Steven L. Taylor, Deon Venter, Simon D. Bowler, Sally Biga, Michael A. McGuckin

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Rationale: The mechanism by which low-dose macrolide therapy reduces exacerbations in non-cystic fibrosis bronchiectasis is not known. Pseudomonas aeruginosa quorum sensing controls the expression of a range of pathogenicity traits and is inhibited by macrolide in vitro. Quorum sensing inhibition renders P. aeruginosa less pathogenic, potentially reducing its contribution to airway damage. Objectives: The aim of this study was to determine whether longterm low-dose erythromycin inhibits P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis. Methods: Analysis was performed on induced sputum from P. aeruginosa-positive subjects at recruitment to the BLESS (Bronchiectasis and Low-Dose Erythromycin Study) trial and after 48 weeks of treatment with erythromycin or placebo. To avoid changes in gene expression during culture, bacterial mRNA was extracted directly from sputum, and the relative expression of functionally critical quorum sensing genes was determined by quantitative polymerase chain reaction. Measurements and Main Results: In keeping with the BLESS study, a significant reduction in total exacerbations was seen in this subgroup (placebo: 6, [interquartile range (IQR), 4-8]; erythromycin: 3, [IQR, 3-4]; P = 0.008; Mann-Whitney test). Erythromycin therapy did not change P. aeruginosa bacterial load determined by polymerase chain reaction. A significant reduction was observed in the expression of the quorum sensing genes, lasR (erythromycin: fold change, 0.065 [IQR, 0.01-0.85], n = 11; placebo: fold change, 1.000 [IQR, 0.05-3.05]; P = 0.047,Mann-Whitney U test) and pqsA (erythromycin: fold change, 0.07 [IQR, 0.02-0.25]; placebo: fold change, 1.000 [IQR, 0.21-4.31], P = 0.017,Mann-WhitneyUtest), after 48 weeks of erythromycin, compared with placebo. Conclusions: We demonstrate inhibition of P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis receiving long-term, low-dose erythromycin, without a reduction in bacterial load, representing a potential mechanism of therapeutic impact beyond a classical antimicrobial or antiinflammatory pathway.

LanguageEnglish
Pages1697-1703
Number of pages7
JournalAnnals of the American Thoracic Society
Volume13
Issue number10
DOIs
Publication statusPublished - 1 Oct 2016

Keywords

  • Bronchiectasis
  • Psuedomonas aeruginosa
  • Quorum sensing

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Burr, Lucy D. ; Rogers, Geraint B. ; Chen, Alice C H ; Hamilton, Brett R. ; Pool, Gertruida F. ; Taylor, Steven L. ; Venter, Deon ; Bowler, Simon D. ; Biga, Sally ; McGuckin, Michael A. / Macrolide treatment inhibits pseudomonas aeruginosa quorum sensing in non-cystic fibrosis bronchiectasis : An analysis from the bronchiectasis and low-dose erythromycin study trial. In: Annals of the American Thoracic Society. 2016 ; Vol. 13, No. 10. pp. 1697-1703.
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abstract = "Rationale: The mechanism by which low-dose macrolide therapy reduces exacerbations in non-cystic fibrosis bronchiectasis is not known. Pseudomonas aeruginosa quorum sensing controls the expression of a range of pathogenicity traits and is inhibited by macrolide in vitro. Quorum sensing inhibition renders P. aeruginosa less pathogenic, potentially reducing its contribution to airway damage. Objectives: The aim of this study was to determine whether longterm low-dose erythromycin inhibits P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis. Methods: Analysis was performed on induced sputum from P. aeruginosa-positive subjects at recruitment to the BLESS (Bronchiectasis and Low-Dose Erythromycin Study) trial and after 48 weeks of treatment with erythromycin or placebo. To avoid changes in gene expression during culture, bacterial mRNA was extracted directly from sputum, and the relative expression of functionally critical quorum sensing genes was determined by quantitative polymerase chain reaction. Measurements and Main Results: In keeping with the BLESS study, a significant reduction in total exacerbations was seen in this subgroup (placebo: 6, [interquartile range (IQR), 4-8]; erythromycin: 3, [IQR, 3-4]; P = 0.008; Mann-Whitney test). Erythromycin therapy did not change P. aeruginosa bacterial load determined by polymerase chain reaction. A significant reduction was observed in the expression of the quorum sensing genes, lasR (erythromycin: fold change, 0.065 [IQR, 0.01-0.85], n = 11; placebo: fold change, 1.000 [IQR, 0.05-3.05]; P = 0.047,Mann-Whitney U test) and pqsA (erythromycin: fold change, 0.07 [IQR, 0.02-0.25]; placebo: fold change, 1.000 [IQR, 0.21-4.31], P = 0.017,Mann-WhitneyUtest), after 48 weeks of erythromycin, compared with placebo. Conclusions: We demonstrate inhibition of P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis receiving long-term, low-dose erythromycin, without a reduction in bacterial load, representing a potential mechanism of therapeutic impact beyond a classical antimicrobial or antiinflammatory pathway.",
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Macrolide treatment inhibits pseudomonas aeruginosa quorum sensing in non-cystic fibrosis bronchiectasis : An analysis from the bronchiectasis and low-dose erythromycin study trial. / Burr, Lucy D.; Rogers, Geraint B.; Chen, Alice C H; Hamilton, Brett R.; Pool, Gertruida F.; Taylor, Steven L.; Venter, Deon; Bowler, Simon D.; Biga, Sally; McGuckin, Michael A.

In: Annals of the American Thoracic Society, Vol. 13, No. 10, 01.10.2016, p. 1697-1703.

Research output: Contribution to journalArticle

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T1 - Macrolide treatment inhibits pseudomonas aeruginosa quorum sensing in non-cystic fibrosis bronchiectasis

T2 - Annals of the American Thoracic Society

AU - Burr, Lucy D.

AU - Rogers, Geraint B.

AU - Chen, Alice C H

AU - Hamilton, Brett R.

AU - Pool, Gertruida F.

AU - Taylor, Steven L.

AU - Venter, Deon

AU - Bowler, Simon D.

AU - Biga, Sally

AU - McGuckin, Michael A.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Rationale: The mechanism by which low-dose macrolide therapy reduces exacerbations in non-cystic fibrosis bronchiectasis is not known. Pseudomonas aeruginosa quorum sensing controls the expression of a range of pathogenicity traits and is inhibited by macrolide in vitro. Quorum sensing inhibition renders P. aeruginosa less pathogenic, potentially reducing its contribution to airway damage. Objectives: The aim of this study was to determine whether longterm low-dose erythromycin inhibits P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis. Methods: Analysis was performed on induced sputum from P. aeruginosa-positive subjects at recruitment to the BLESS (Bronchiectasis and Low-Dose Erythromycin Study) trial and after 48 weeks of treatment with erythromycin or placebo. To avoid changes in gene expression during culture, bacterial mRNA was extracted directly from sputum, and the relative expression of functionally critical quorum sensing genes was determined by quantitative polymerase chain reaction. Measurements and Main Results: In keeping with the BLESS study, a significant reduction in total exacerbations was seen in this subgroup (placebo: 6, [interquartile range (IQR), 4-8]; erythromycin: 3, [IQR, 3-4]; P = 0.008; Mann-Whitney test). Erythromycin therapy did not change P. aeruginosa bacterial load determined by polymerase chain reaction. A significant reduction was observed in the expression of the quorum sensing genes, lasR (erythromycin: fold change, 0.065 [IQR, 0.01-0.85], n = 11; placebo: fold change, 1.000 [IQR, 0.05-3.05]; P = 0.047,Mann-Whitney U test) and pqsA (erythromycin: fold change, 0.07 [IQR, 0.02-0.25]; placebo: fold change, 1.000 [IQR, 0.21-4.31], P = 0.017,Mann-WhitneyUtest), after 48 weeks of erythromycin, compared with placebo. Conclusions: We demonstrate inhibition of P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis receiving long-term, low-dose erythromycin, without a reduction in bacterial load, representing a potential mechanism of therapeutic impact beyond a classical antimicrobial or antiinflammatory pathway.

AB - Rationale: The mechanism by which low-dose macrolide therapy reduces exacerbations in non-cystic fibrosis bronchiectasis is not known. Pseudomonas aeruginosa quorum sensing controls the expression of a range of pathogenicity traits and is inhibited by macrolide in vitro. Quorum sensing inhibition renders P. aeruginosa less pathogenic, potentially reducing its contribution to airway damage. Objectives: The aim of this study was to determine whether longterm low-dose erythromycin inhibits P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis. Methods: Analysis was performed on induced sputum from P. aeruginosa-positive subjects at recruitment to the BLESS (Bronchiectasis and Low-Dose Erythromycin Study) trial and after 48 weeks of treatment with erythromycin or placebo. To avoid changes in gene expression during culture, bacterial mRNA was extracted directly from sputum, and the relative expression of functionally critical quorum sensing genes was determined by quantitative polymerase chain reaction. Measurements and Main Results: In keeping with the BLESS study, a significant reduction in total exacerbations was seen in this subgroup (placebo: 6, [interquartile range (IQR), 4-8]; erythromycin: 3, [IQR, 3-4]; P = 0.008; Mann-Whitney test). Erythromycin therapy did not change P. aeruginosa bacterial load determined by polymerase chain reaction. A significant reduction was observed in the expression of the quorum sensing genes, lasR (erythromycin: fold change, 0.065 [IQR, 0.01-0.85], n = 11; placebo: fold change, 1.000 [IQR, 0.05-3.05]; P = 0.047,Mann-Whitney U test) and pqsA (erythromycin: fold change, 0.07 [IQR, 0.02-0.25]; placebo: fold change, 1.000 [IQR, 0.21-4.31], P = 0.017,Mann-WhitneyUtest), after 48 weeks of erythromycin, compared with placebo. Conclusions: We demonstrate inhibition of P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis receiving long-term, low-dose erythromycin, without a reduction in bacterial load, representing a potential mechanism of therapeutic impact beyond a classical antimicrobial or antiinflammatory pathway.

KW - Bronchiectasis

KW - Psuedomonas aeruginosa

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