The consequences of O-acetylated
alginate-producing Pseudomonas aeruginosa biofilms in the lungs of chronically infected
cystic fibrosis (CF) patients are tolerance to both
antibiotic treatments and effects on the innate and the adaptive defense mechanisms. In clinical trials,
azithromycin (AZM) has been shown to improve the lung function of CF patients. The present study was conducted in accordance with previous in vitro studies suggesting that the effect of AZM may be the inhibition of
alginate production, blockage of quorum sensing (QS), and increased sensitivity to
hydrogen peroxide and the
complement system. Moreover, we show that AZM may affect the polymerization of P. aeruginosa
alginate by the incomplete precipitation of polymerized
alginate and high levels of readily dialyzable
uronic acids. In addition, we find that mucoid bacteria in the stationary growth phase became sensitive to AZM, whereas cells in the exponential phase did not. Interestingly, AZM-treated P. aeruginosa lasI mutants appeared to be particularly resistant to serum, whereas bacteria with a functional QS system did not. We show in a CF mouse model of chronic P. aeruginosa lung
infection that AZM treatment results in the suppression of QS-regulated
virulence factors, significantly improves the clearance of P. aeruginosa
alginate biofilms, and reduces the severity of the lung pathology compared to that in control mice. We conclude that AZM attenuates the virulence of P. aeruginosa, impairs its ability to form fully polymerized
alginate biofilms, and increases its sensitivity to
complement and stationary-phase killing, which may explain the clinical efficacy of AZM.