Sodium Nitrite-Mediated Killing of the Major Cystic Fibrosis Pathogens Pseudomonas aeruginosa , Staphylococcus aureus , and Burkholderia cepacia under Anaerobic Planktonic and Biofilm Conditions

Abstract

A hallmark of airways in patients with cystic fibrosis (CF) is highly refractory, chronic infections by several opportunistic bacterial pathogens. A recent study demonstrated that acidified sodium nitrite (A-NO 2 − ) killed the highly refractory mucoid form of Pseudomonas aeruginosa , a pathogen that significantly compromises lung function in CF patients (S. S. Yoon et al., J. Clin. Invest. 116: 436-446, 2006). Therefore, the microbicidal activity of A-NO 2 − (pH 6.5) against the following three major CF pathogens was assessed: P. aeruginosa (a mucoid, mucA22 mutant and a sequenced nonmucoid strain, PAO1), Staphylococcus aureus USA300 (methicillin resistant), and Burkholderia cepacia , a notoriously antibiotic-resistant organism. Under planktonic, anaerobic conditions, growth of all strains except for P. aeruginosa PAO1 was inhibited by 7.24 mM (512 μg ml −1 NO 2 − ). B. cepacia was particularly sensitive to low concentrations of A-NO 2 − (1.81 mM) under planktonic conditions. In antibiotic-resistant communities known as biofilms, which are reminiscent of end-stage CF airway disease, A-NO 2 − killed mucoid P. aeruginosa , S. aureus , and B. cepacia ; 1 to 2 logs of cells were killed after a 2-day incubation with a single dose of ∼15 mM A-NO 2 − . Animal toxicology and phase I human trials indicate that these bactericidal levels of A-NO 2 − can be easily attained by aerosolization. Thus, in summary, we demonstrate that A-NO 2 − is very effective at killing these important CF pathogens and could be effective in other infectious settings, particularly under anaerobic conditions where bacterial defenses against the reduction product of A-NO 2 − , nitric oxide (NO), are dramatically reduced.