Pseudomonas aeruginosa, an opportunistic pathogen, is the third most common pathogen associated with nosocomial urinary tract infections (UTIs). The virulence of this organism is due to its ability to produce quorum-sensing (QS) signal molecules and form biofilms. These biofilms are usually resistant to conventional antibiotics and host immune responses. Recently, beneficial effects of macrolides, especially azithromycin (AZM), have been shown in patients suffering from chronic infections caused by P. aeruginosa. These were due to anti-inflammatory and modulatory effects of AZM on the expression of virulence factors of this pathogen. The present study was designed to evaluate the potential of AZM to inhibit QS signal molecules and its ability to attenuate the virulence of P. aeruginosa in an experimental UTI model. Sub-MIC concentrations of AZM significantly inhibited the production of QS signals, swimming, swarming and twitching motilities, and biofilm formation in vitro. The therapeutic evaluation of AZM in this experimental UTI model showed complete clearance of the organisms from the mouse kidneys. The results of this study highlight the potential effectiveness of AZM in attenuating the virulence of P. aeruginosa in a UTI model.
INTRODUCTIONQuorum sensing (QS) is an important global gene regulatory mechanism in bacteria that enables individual bacteria to coordinate their behaviour in populations. The QS system relies on self-generated signalling molecules, which coordinate gene expression in response to population density (Rumbaugh et al., 2000). Many processes that assist in the survival, persistence and pathogenesis of Pseudomonas aeruginosa, such as the expression of virulence factors and biofilm formation, are under the control of QS. Two interrelated QS systems, las and rhl, have been reported in P. aeruginosa and act in a hierarchical manner (Davies et al., 1998;Favre-Bonté et al., 2003;de Kievit, 2009). Both systems consist of inducer and regulatory proteins and a cognate autoinducer signal molecule, N-(3-oxododecanoyl) homoserine lactone (OdDHL) and N-butanoyl homoserine lactone (BHL), respectively (Rumbaugh et al., 2000;Venturi, 2006). P. aeruginosa causes infections in a variety of situations, such as cystic fibrosis, burns, cancer and traumatic wounds, especially in immunocompromised hosts, and can be a problem in intensive care units (Van Delden & Iglewski, 1998;Singh et al., 2000;Ehrlich et al., 2002). It has a tendency to form biofilms on biotic and abiotic surfaces such as catheters and lead to persistent and chronic urinary tract infections (UTIs) (Donlan & Costerton, 2002;Willcox et al., 2008). These biofilms are usually resistant to antibiotics and host immune defence clearance, and hence are difficult to eradicate by antibiotic intervention (Ceri et al., 1999;Costerton et al., 1999;Donlan, 2001).Although antibiotic therapy has great benefits in treatment, the emergence of multidrug resistance in P. aeruginosa has left clinicians with limited therapeutic options. Azithromycin (AZM), a memb...
