This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hoffmann, N.
Right arrow Articles by Høiby, N.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hoffmann, N.
Right arrow Articles by Høiby, N.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, October 2007, p. 3677-3687, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.01011-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Azithromycin Blocks Quorum Sensing and Alginate Polymer Formation and Increases the Sensitivity to Serum and Stationary-Growth-Phase Killing of Pseudomonas aeruginosa and Attenuates Chronic P. aeruginosa Lung Infection in Cftr–/– Mice{triangledown}

Nadine Hoffmann,1* Baoleri Lee,1 Morten Hentzer,2 Thomas Bovbjerg Rasmussen,2 Zhijun Song,1 Helle Krogh Johansen,1 Michael Givskov,2 and Niels Høiby1

Department of Clinical Microbiology, Rigshospitalet, and Department of Bacteriology, Institute for Medical Microbiology and Immunology, Panum Institute, University of Copenhagen, DK-2100 Copenhagen, Denmark,1 Center for Biomedical Microbiology, BioCentrum-DTU, Building 301, Technical University of Denmark, DK-2800 Lyngby, Denmark2

Received 13 August 2006/ Returned for modification 27 March 2007/ Accepted 30 June 2007

The consequences of O-acetylated alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected cystic fibrosis (CF) patients are tolerance to both antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials, azithromycin (AZM) has been shown to improve the lung function of CF patients. The present study was conducted in accordance with previous in vitro studies suggesting that the effect of AZM may be the inhibition of alginate production, blockage of quorum sensing (QS), and increased sensitivity to hydrogen peroxide and the complement system. Moreover, we show that AZM may affect the polymerization of P. aeruginosa alginate by the incomplete precipitation of polymerized alginate and high levels of readily dialyzable uronic acids. In addition, we find that mucoid bacteria in the stationary growth phase became sensitive to AZM, whereas cells in the exponential phase did not. Interestingly, AZM-treated P. aeruginosa lasI mutants appeared to be particularly resistant to serum, whereas bacteria with a functional QS system did not. We show in a CF mouse model of chronic P. aeruginosa lung infection that AZM treatment results in the suppression of QS-regulated virulence factors, significantly improves the clearance of P. aeruginosa alginate biofilms, and reduces the severity of the lung pathology compared to that in control mice. We conclude that AZM attenuates the virulence of P. aeruginosa, impairs its ability to form fully polymerized alginate biofilms, and increases its sensitivity to complement and stationary-phase killing, which may explain the clinical efficacy of AZM.

* Corresponding author. Mailing address: Department of Bacteriology, Institute for Medical Microbiology and Immunology, Panum Institute 24.1, University of Copenhagen, DK-2100 Copenhagen, Denmark. Phone: (45) 3532 7890. Fax: (45) 3532 7693. E-mail: nadinehof{at}hotmail.com

{triangledown} Published ahead of print on 9 July 2007.

Antimicrobial Agents and Chemotherapy, October 2007, p. 3677-3687, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.01011-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Presterl, E., Hajdu, S., Lassnigg, A. M., Hirschl, A. M., Holinka, J., Graninger, W. (2009). Effects of Azithromycin in Combination with Vancomycin, Daptomycin, Fosfomycin, Tigecycline, and Ceftriaxone on Staphylococcus epidermidis Biofilms. Antimicrob. Agents Chemother. 53: 3205-3210 [Abstract] [Full Text]  
  • Zhang, M., Jiao, X.-d., Hu, Y.-h., Sun, L. (2009). Attenuation of Edwardsiella tarda Virulence by Small Peptides That Interfere with LuxS/Autoinducer Type 2 Quorum Sensing. Appl. Environ. Microbiol. 75: 3882-3890 [Abstract] [Full Text]  
  • Mulet, X., Macia, M. D., Mena, A., Juan, C., Perez, J. L., Oliver, A. (2009). Azithromycin in Pseudomonas aeruginosa Biofilms: Bactericidal Activity and Selection of nfxB Mutants. Antimicrob. Agents Chemother. 53: 1552-1560 [Abstract] [Full Text]  
  • Parks, Q. M., Young, R. L., Poch, K. R., Malcolm, K. C., Vasil, M. L., Nick, J. A. (2009). Neutrophil enhancement of Pseudomonas aeruginosa biofilm development: human F-actin and DNA as targets for therapy. J Med Microbiol 58: 492-502 [Abstract] [Full Text]  
  • Idris, S. F, Chilvers, E. R, Haworth, C., McKeon, D., Condliffe, A. M (2009). Azithromycin therapy for neutrophilic airways disease: myth or magic?. Thorax 64: 186-189 [Full Text]  
  • Molina, A., Del Campo, R., Maiz, L., Morosini, M.-I., Lamas, A., Baquero, F., Canton, R. (2008). High prevalence in cystic fibrosis patients of multiresistant hospital-acquired methicillin-resistant Staphylococcus aureus ST228-SCCmecI capable of biofilm formation. J Antimicrob Chemother 62: 961-967 [Abstract] [Full Text]  
  • Skindersoe, M. E., Alhede, M., Phipps, R., Yang, L., Jensen, P. O., Rasmussen, T. B., Bjarnsholt, T., Tolker-Nielsen, T., Hoiby, N., Givskov, M. (2008). Effects of Antibiotics on Quorum Sensing in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 52: 3648-3663 [Abstract] [Full Text]  
  • Murphy, B. S., Sundareshan, V., Cory, T. J., Hayes, D. Jr, Anstead, M. I., Feola, D. J. (2008). Azithromycin alters macrophage phenotype. J Antimicrob Chemother 61: 554-560 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»