title: Macrolide Treatment Inhibits Pseudomonas aeruginosa Quorum Sensing in Non-Cystic Fibrosis Bronchiectasis. An Analysis from the Bronchiectasis and Low-Dose Erythromycin Study Trial.
abstract: 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.
  
  
  
  The aim of this study was to determine whether long-term low-dose erythromycin inhibits P. aeruginosa quorum sensing within the airways of patients with non-cystic fibrosis bronchiectasis.
  
  
  
  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.
  
  
  
  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-Whitney U test), after 48 weeks of erythromycin, compared with placebo.
  
  
  
  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.
authors.affiliation: 1 Immunity, Infection and Inflammation Program, Mater Research Institute, University of Queensland, Translational Research Institute, Wooloongabba, Queensland, Australia.|4 Department of Respiratory Medicine, and.
authors.forename: Lucy D
authors.identifier: 0000-0003-4010-3787
authors.initials: LD
authors.lastname: Burr
authors.affiliation: 2 South Australian Health and Medical Research Institute Infection and Immunity Theme, School of Medicine, Flinders University, Adelaide, Australia; and.
authors.forename: Geraint B
authors.initials: GB
authors.lastname: Rogers
authors.affiliation: 1 Immunity, Infection and Inflammation Program, Mater Research Institute, University of Queensland, Translational Research Institute, Wooloongabba, Queensland, Australia.
authors.forename: Alice C-H
authors.initials: AC
authors.lastname: Chen
authors.affiliation: 3 OMICS, Pathology Department.
authors.forename: Brett R
authors.initials: BR
authors.lastname: Hamilton
authors.affiliation: 3 OMICS, Pathology Department.
authors.forename: Gertruida F
authors.initials: GF
authors.lastname: Pool
authors.affiliation: 2 South Australian Health and Medical Research Institute Infection and Immunity Theme, School of Medicine, Flinders University, Adelaide, Australia; and.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Taylor
authors.affiliation: 3 OMICS, Pathology Department.
authors.forename: Deon
authors.initials: D
authors.lastname: Venter
authors.affiliation: 4 Department of Respiratory Medicine, and.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Bowler
authors.affiliation: 5 Department of Microbiology, Mater Health Services, South Brisbane, Queensland, Australia.
authors.forename: Sally
authors.initials: S
authors.lastname: Biga
authors.affiliation: 1 Immunity, Infection and Inflammation Program, Mater Research Institute, University of Queensland, Translational Research Institute, Wooloongabba, Queensland, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
mesh_terms: D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D001315:Australia; D058491:Bacterial Load; D001987:Bronchiectasis / Q000188:drug therapy / Q000382:microbiology*; D004311:Double-Blind Method; D004917:Erythromycin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011552:Pseudomonas Infections / Q000188:drug therapy*; D011550:Pseudomonas aeruginosa; D053038:Quorum Sensing / Q000187:drug effects*; D012137:Respiratory System / Q000187:drug effects / Q000382:microbiology; D013183:Sputum / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D004917:Erythromycin
keywords: Psuedomonas aeruginosa; bronchiectasis; quorum sensing