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Antimicrobial Agents and Chemotherapy, October 2008, p. 3648-3663, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.01230-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Effects of Antibiotics on Quorum Sensing in Pseudomonas aeruginosa{triangledown}

Mette E. Skindersoe,1,{dagger} Morten Alhede,1 Richard Phipps,1 Liang Yang,1 Peter O. Jensen,3 Thomas B. Rasmussen,2 Thomas Bjarnsholt,1 Tim Tolker-Nielsen,1 Niels Høiby,3 and Michael Givskov1*

Biomedical Microbiology, BioSys, Bldg. 227, Technical University of Denmark, Kgs. Lyngby DK-2800,1 Physiology, Cultures & Enzymes Division, Chr-Hansen A/S, Bøge Allé 10-12, Hørsholm DK-2970,2 Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen DK-2100, Denmark3

Received 19 September 2007/ Returned for modification 23 October 2007/ Accepted 11 June 2008

During infection, Pseudomonas aeruginosa employs bacterial communication (quorum sensing [QS]) to coordinate the expression of tissue-damaging factors. QS-controlled gene expression plays a pivotal role in the virulence of P. aeruginosa, and QS-deficient mutants cause less severe infections in animal infection models. Treatment of cystic fibrosis (CF) patients chronically infected with P. aeruginosa with the macrolide antibiotic azithromycin (AZM) has been demonstrated to improve the clinical outcome. Several studies indicate that AZM may accomplish its beneficial action in CF patients by impeding QS, thereby reducing the pathogenicity of P. aeruginosa. This led us to investigate whether QS inhibition is a common feature of antibiotics. We present the results of a screening of 12 antibiotics for their QS-inhibitory activities using a previously described QS inhibitor selector 1 strain. Three of the antibiotics tested, AZM, ceftazidime (CFT), and ciprofloxacin (CPR), were very active in the assay and were further examined for their effects on QS-regulated virulence factor production in P. aeruginosa. The effects of the three antibiotics administered at subinhibitory concentrations were investigated by use of DNA microarrays. Consistent results from the virulence factor assays, reverse transcription-PCR, and the DNA microarrays support the finding that AZM, CFT, and CPR decrease the expression of a range of QS-regulated virulence factors. The data suggest that the underlying mechanism may be mediated by changes in membrane permeability, thereby influencing the flux of N-3-oxo-dodecanoyl-L-homoserine lactone.

* Corresponding author. Mailing address: Biomedical Microbiology, BioSys, Bldg 227, Technical University of Denmark, Kgs. Lyngby DK-2800, Denmark. Phone: 45 4525 2769. Fax: 45 4593 2809. E-mail: immg{at}pop.dtu.dk

{triangledown} Published ahead of print on 21 July 2008.

{dagger} Present address: ChemoMetec A/S, Gydevang 43, DK-3450 Alleroed, Denmark.

Antimicrobial Agents and Chemotherapy, October 2008, p. 3648-3663, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.01230-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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