Quorum-Sensing Antagonistic Activities of Azithromycin in Pseudomonas aeruginosa PAO1: a Global Approach

Abstract

The administration of macrolides such as azithromycin for chronic pulmonary infection of cystic fibrosis patients has been reported to be of benefit. Although the mechanisms of action remain obscure, anti-inflammatory effects as well as interference of the macrolide with Pseudomonas aeruginosa virulence factor production have been suggested to contribute to an improved clinical outcome. In this study we used a systematic approach and analyzed the impact of azithromycin on the global transcriptional pattern and the protein expression profile of P. aeruginosa PAO1 cultures versus those in untreated controls. The most remarkable result of this study is the finding that azithromycin exhibited extensive quorum-sensing antagonistic activities. In accordance with the inhibition of the quorum-sensing systems, virulence factor production was diminished and the oxidative stress response was impaired, whereas the type III secretion system was strongly induced. Moreover, P. aeruginosa motility was reduced, which probably accounts for the previously observed impaired biofilm formation capabilities of azithromycin-treated cultures. The interference of azithromycin with quorum-sensing-dependent virulence factor production, biofilm formation, and oxidative stress resistance in P. aeruginosa holds great promise for macrolide therapy in cystic fibrosis. Clearly quorum-sensing antagonist macrolides should be paid more attention in the management of chronic P. aeruginosa infections, and as quorum-sensing antagonists, macrolides might gain vital importance for more general application against chronic infections.

Azithromycin Reduces the Production of α-hemolysin and Biofilm Formation in Staphylococcus aureus

“…Macrolide antibiotics have been shown to act as QS inhibitors at subinhibitory concentrations. For example, erythromycin has been reported to suppress production of P. aeruginosa hemagglutinins, protease, hemolysin and AHL signals [14], and studies have shown that azithromycin at sub-MIC concentrations affects QS-regulated virulence genes and biofilm formation in vitro [15][16][17] and in in vivo models of disease [18]. In the present study, we demonstrate that sub-inhibitory concentrations of azithromycin could dose-dependently reduce the haemolytic activity and biofilm formation in S. aureus.…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…These reductions coincided with reduced Las-and Rhl-dependent gene transcription and have been corroborated by microarray and proteomic studies (319,320), which found, in addition to QS gene misregulation, a reduction in levels of oxidative stress and motility-related genes but an increase in type III secretion (TTS)-related genes. The diminished response to oxidative stress conditions may account for the reduced cell viability in late stationary phase that was reported to occur with increasing concentrations of macrolides (318,319). Likewise, the finding that TTS was induced with exposure to AZM may explain the paradoxical finding that pretreatment of bacterial cultures with macrolides prior to intranasal inoculation in mice led to an enhanced lethal effect (321).…”

Antimicrobial Effect of Fluoroquinolones for the Eradication of Nontypeable Haemophilus Influenzae Isolates within Biofilms

“…Since the use of fl uoroquinolones in young children is limited in many countries because of adverse neurological side effects, the clinical antimicrobial effectiveness against BLNAS and BLNAR NTHi in biofi lms has not been confi rmed. AMP, CTX, ERY and CLR had no signifi cant effect against either BLNAS or BLNAR NTHi biofi lms, although it has been reported that macrolides have an inhibitory effect on P. aeruginosa biofi lm formation and survival cells in biofi lm (Favre-Bonté et al 2003;Nalca et al 2006). …”