zithromax and bis(3--5-)-cyclic-diguanylic-acid

Macrolides have been reported to exert a variety of effects on both host immunomodulation and repression of bacterial pathogenicity. In this study, we report that the 3',5'-cyclic diguanylic acid (c-di-GMP) signaling system, which regulates virulence in Pseudomonas aeruginosa, is affected by the macrolide azithromycin. Using DNA microarray analysis, we selected a gene encoding PA2567 related to c-di-GMP metabolism that was significantly affected by azithromycin treatment. Expression of the PA2567 gene was significantly repressed by azithromycin in a time- and dose-dependent manner, whereas no difference in PA2567 gene expression was observed in the absence of azithromycin. In-frame deletion of the PA2567 gene affected both virulence factors and the quorum-sensing system, and significantly decreased total bacteria in a mouse pneumonia model compared to the wild-type strain (P < 0.05). These results suggest that macrolides possess the ability to modulate c-di-GMP intracellular signaling in P. aeruginosa.

Topics: Animals; Anti-Bacterial Agents; Azithromycin; Bacterial Proteins; Colony Count, Microbial; Cyclic GMP; Disease Models, Animal; Female; Mice; Mice, Inbred C57BL; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Signal Transduction; Virulence Factors