1-hydroxyphenazine and Disease-Models--Animal

Pathogenic bacteria demonstrate incredible abilities to evade conventional antibiotics through the development of resistance and formation of dormant, surface-attached biofilms. Therefore, agents that target and eradicate planktonic and biofilm bacteria are of significant interest. We explored a new series of halogenated phenazines (HP) through the use of

Topics: Aniline Compounds; Animals; Anti-Bacterial Agents; Biofilms; Cell Line; Cell Survival; Disease Models, Animal; Drug Design; Female; Halogenation; Humans; Iron; Iron Deficiencies; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Phenazines; Staphylococcal Infections; Structure-Activity Relationship; Wound Healing

We previously showed that the supernatant of a Pseudomonas aeruginosa (PA) culture and its constituents pyocyanin and 1-hydroxyphenazine inhibit ciliary activity of dispersed tracheal epithelial cells in vitro via the generation of oxygen radicals by phagocytes. In the present study, we wished to determine if tracheal mucus velocity (TMV) is also impaired by PA supernatant and if oxygen radicals have a mediating role. In conscious sheep, TMV (measured with a radiographic method) was determined before and serially following aerosol challenge with the cell-free supernatant of a PA culture or unconditioned culture medium (control). TMV decreased from a mean (+/- SEM) baseline of 6.7 +/- 1.1 mm/min (n = 6) by 29, 35, and 25% at 0.5, 3, and 24 h after challenge, respectively (p < 0.05), and returned to baseline 1 wk later (-6%, p = NS). Control medium had no effect on TMV (maximum decrease by 15% at 0.5 h). Aerosolized catalase blunted the effect of PA supernatant on TMV. To determine if the impairment of TMV involved ciliary inhibition, tissues were mounted in a chamber and ciliary beat frequency (CBF) and surface liquid velocity (SLV) were measured with a microscopic method. PA supernatant decreased both CBF (maximum mean decrease 12%; n = 5, p < 0.05) and SLV (maximum mean decrease 78%; n = 5, p < 0.05) in a dose-dependent fashion, with a correlation between the two parameters; these effects were blocked by catalase.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Inhalation; Animals; Catalase; Disease Models, Animal; Evaluation Studies as Topic; Female; Free Radicals; Mucociliary Clearance; Phenazines; Pseudomonas aeruginosa; Pyocyanine; Radiography; Sheep; Trachea