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JAC Advance Access originally published online on April 29, 2004
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Journal of Antimicrobial Chemotherapy (2004) 53, 1054-1061
© 2004 The British Society for Antimicrobial Chemotherapy

Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice

H. Wu1,*, Z. Song1, M. Hentzer2, J. B. Andersen2, S. Molin2, M. Givskov2 and N. Høiby1

1 Department of Clinical Microbiology, University Hospital of Copenhagen (Rigshospitalet), Juliane Marie Vej 22, Copenhagen Ø, DK-2100; 2 Molecular Microbiology, Building 301, BioCentrum, The Technical University of Denmark, Lyngby, DK-2800, Denmark

Received 20 September 2003; returned 20 November 2003; revised 29 February 2004; accepted 4 March 2004

Introduction: Antibiotics are used to treat bacterial infections by killing the bacteria or inhibiting their growth, but resistance to antibiotics can develop readily. The discovery that bacterial quorum-sensing regulates bacterial virulence as well as the formation of biofilms opens up new ways to control certain bacterial infections. Furanone compounds capable of inhibiting bacterial quorum-sensing systems have been isolated from the marine macro alga Delisea pulchra.

Objectives: Two synthetic furanones were tested for their ability to attenuate bacterial virulence in the mouse models of chronic lung infection by targeting bacterial quorum-sensing without directly killing bacteria or inhibiting their growth.

Methods: Study I. Mice with Escherichia coli MT102 [luxR-PluxI-gfp(ASV)] lung infection were injected intravenously with N-acyl homoserine lactones with or without furanones to test the interference of furanones with quorum-sensing. Study II. Mice with lung infection by Pseudomonas aeruginosa PAO1 [dsred, lasR-PlasB-gfp(ASV)] were injected intravenously with furanones to evaluate their inhibiting effects on quorum-sensing. Study III. Mice with P. aeruginosa PAO1 lung infection were treated with different doses of furanones to evaluate the therapeutic effects of furanones on the lung infection.

Results: Furanones successfully interfered with N-acyl homoserine lactone and suppressed bacterial quorum-sensing in lungs, which resulted in decreases in expression of green fluorescent protein. Furanones accelerated lung bacterial clearance, and reduced the severity of lung pathology. In a lethal P. aeruginosa lung infection, treatment with furanone significantly prolonged the survival time of the mice.

Conclusion: Synthetic furanone compounds inhibited bacterial quorum-sensing in P. aeruginosa and exhibited favourable therapeutic effects on P. aeruginosa lung infection.

Keywords: antibiotic resistance, acyl-homoserine lactones, green fluorescent protein, GFP, mouse models

* Corresponding author. Tel: +45-35456428; Fax: +45-35456412; E-mail: wuhong{at}get2net.dk


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