Influence of macrolides on mucoid alginate biosynthetic enzyme from Pseudomonas aeruginosa

Abstract

OBJECTIVE: The long-term administration of erythromycin (EM), clarithromycin (CAM) or azithromycin (AZM) has generally resulted in a favorable outcome for patients with diffuse panbronchiolitis (DPB) infected with mucoid Pseudomonas aeruginosa. To elucidate the mechanism involved, the influence of macrolides on mucoid alginate production by P. aeruginosa was investigated in vitro. METHODS: The macrolides used in this study were EM with a 14-membered ring, AZM with a 15-membered ring, midecamycin (MDM) with a 16-membered ring, and CP-4305, which has had mycarose removed from MDM, The effects of macrolides on mucoid P. aeruginosa were investigated by quantitative assay of alginate production and inhibition of guanosine diphospho-D-mannose dehydrogenase activity. RESULTS: After incubation with EM, AZM and CP-4305, the structural material of P. aeruginosa biofilm was distorted, and the enzymatic activity of GDP-D-mannose dehydrogenase, the most important enzyme in mucoid alginate biosynthesis, was inhibited. However, these effects were not observed with the 16-membered macrolide MDM. CONCLUSIONS: The basic mechanism of clinical efficacy seen characteristically in 14- or 15-membered macrolides for patients with airway biofilm disease depends on the ability of such macrolides to inhibit alginate production by P. aeruginosa. Furthermore, this suggests that the inhibitory effect observed with 14-, 15- and 16-membered macrolides may depend on the sugar chain connected with the macrolide ring.

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

“…While flagellum-mediated motility has been implicated to be required to bring P. aeruginosa within proximity of a surface, type IV pili by virtue of twitching motility enable P. aeruginosa to migrate across a surface, recruit cells from adjacent monolayers, and form cell aggregates (31), thus contributing to biofilm formation. The observed impaired swimming and twitching motility of AZM-treated PAO1 could explain the previous observations that AZM delays biofilm formation, as evidenced by decreased biomass (6) and impaired alginate production (12,27).…”

Antibacterial Therapy for Acute and Chronic Diseases of the Upper Respiratory Tract in Adults

“…Полимикробные сообщества, отграниченные от внешней среды и погруженные в образованный ими защитный внеклеточный полимерный матрикс, т. е. обра-зующие биопленку, недоступны для действия многих антибиотиков. Однако макролиды тормозят образование альгината биопленок, что и обеспечивает их клиническую эффективность при воздействии на полимикробные сообщества, защищенные биопленкой [31]. Макролиды являются одной из самых безопасных групп антибиоти-ков.…”

Adverse Influences of Antimicrobial Strategy against Mature Oral Biofilm

“…Although Pseudomonas aeruginosa that contributes to progress respiratory infection is resistant to azithromycin, low-dose azithromycin has been shown to inhibit protein synthesis [49] and improve clinical symptom [50,51]. Sub-MIC concentrations of azithromycin have also been shown to inhibit quorum sensing and alginate production [52,53].…”