Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulating effects. Long-term azithromycin therapy in patients with chronic lung diseases such as cystic fibrosis has been associated with increased antimicrobial resistance, emergence of hypermutable strains, ototoxicity, and cardiac toxicity. The aim of this study is to assess the antiinflammatory effects of the non-antibiotic azithromycin derivative CSY0073.

EXPERIMENTAL APPROACH: We compared CSY0073 and azithromycin in experiments on bacterial cultures, Pseudomonas aeruginosa biofilm, lung cells, and mice challenged intranasally with P. aeruginosa lipopolysaccharide (LPS).

KEY RESULTS: In contrast to azithromycin, CSY0073 did not inhibit the growth of P. aeruginosa, Staphylococcus aureus, or Haemophilus influenzae and had no effect on established P. aeruginosa biofilm. Bronchoalveolar lavage fluids and lung homogenates collected after the LPS challenge in mice showed that CSY0073 and azithromycin (intraperitoneal administration, 200 mg/kg) induced decreases in neutrophil counts at 24h and TNFα, CXCL-1 and CXCL-2 levels in the BAL fluid after 3 hours and in IL-6, CXCL-2 and IL-1β levels in the lung after 3 hours compared to the vehicle. Only azithromycin reduces IL-1β level in the lung 24h post LPS challenge. CSY0073 and azithromycin similarly diminished the production of proinflammatory cytokines by macrophages, but not lung epithelial cells, exposed to P. aeruginosa LPS.

CONCLUSIONS AND IMPLICATIONS: CSY0073 has no antibacterial effects but shares the anti-inflammatory profile of azithromycin. CSY0073 may hold promise for the long-term treatment of patients with chronic lung diseases.