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Ribosome Protection Prevents Azithromycin-Mediated Quorum-Sensing Modulation and Stationary-Phase Killing of Pseudomonas aeruginosa

Department of Microbiology and Molecular Medicine, University of Geneva, and Service of Infectious Diseases, University Hospital, Geneva, Switzerland

Received 10 May 2007/ Returned for modification 3 July 2007/ Accepted 2 September 2007

In Pseudomonas aeruginosa, azithromycin has been shown to reduce virulence factor production, to retard biofilm formation, and to exhibit bactericidal effects on stationary-phase cells. In this study we analyzed whether these azithromycin-mediated effects require interaction with the ribosome. We blocked the access of azithromycin to the ribosome in P. aeruginosa PAO1 by expressing the 23S rRNA methylase ErmBP from Clostridium perfringens. Ribosome protection prevented the azithromycin-mediated reduction of elastase and rhamnolipid production, as well as the inhibition of swarming motility. Ribosome protection also prevented the killing of stationary-phase cells, suggesting that the cell-killing effect of azithromycin does not result solely from membrane destabilization. We further show that rhamnolipids are involved in cell killing, probably by increasing the uptake of the hydrophobic azithromycin molecule. These results have important implications for the treatment with azithromycin of patients chronically colonized by P. aeruginosa and might explain the variability in the efficacy of azithromycin treatments.

Published ahead of print on 17 September 2007.