Cystic Fibrosis Therapeutic

Colonization of the lungs by biofilm-forming pathogens is a major cause of mortality in cystic fibrosis, CF. In CF patients, these pathogens are difficult to treat due to the additional protection provided by both the biofilm exopolysaccharide matrix and thick, viscous mucus.

In work published in ACS Infectious Diseases, Mona Ahonen and her colleagues in the Schoenfisch Group evaluated the antibiofilm efficacy of nitric oxide-releasing alginates against Pseudomonas aeruginosa, Burkholderia cepacia, Staphylococcus aureus, and methicillin-resistant S. aureus biofilms in both aerobic and anaerobic environments.

Varying the amine precursor grafted onto alginate oligosaccharides imparted tunable nitric oxide, NO, storage, ∼0.1–0.3 μmol/mg, and release kinetics, ∼4–40 min half-lives, in the artificial sputum media used for biofilm testing. The NO-releasing alginates were highly antibacterial against the four CF-relevant pathogens, achieving a 5-log reduction in biofilm viability after 24 h of treatment, with biocidal efficacy dependent on NO-release kinetics.

Aerobic biofilms required greater starting NO doses to achieve killing relative to the anaerobic biofilms. Relative to tobramycin, the minimum concentration of antibacterial agent required to achieve a 5-log reduction in viability after 24hrs, MBEC24h, of ≥2000 μg/mL, and vancomycin, MBEC24h ≥ 1000 μg/mL, the NO-releasing alginates proved to be more effective, NO dose ≤ 520 μg/mL, regardless of growth conditions.

Combined with the ability of alginate oligosaccharides to decrease mucus viscoelasticity, these results suggest broader utility of NO-releasing alginates as a dual-action CF therapeutic. In particular, NO release may be able to eradicate biofilms embedded deep within the mucus layer where low oxygen concentrations reduce the efficacy of currently employed antibiotics.