Anaerobic killing of mucoid Pseudomonas aeruginosa by acidified nitrite derivatives under cystic fibrosis airway conditions

Sun Yoon Sang, Ray Coakley, Gee W. Lau, Sergei V. Lymar, Benjamin Gaston, Ahmet C. Karabulut, Robert F. Hennigan, Sung Hei Hwang, Garry Buettner, Michael J. Schurr, Joel E. Mortensen, Jane L. Burns, David Speert, Richard C. Boucher, Daniel J. Hassett

Research output: Contribution to journalArticle

Abstract

Mucoid, mucA mutant Pseudomonas aeruginosa cause chronic lung infections in cystic fibrosis (CF) patients and are refractory to phagocytosis and antibiotics. Here we show that mucoid bacteria perish during anaerobic exposure to 15 mM nitrite (NO2 -) at pH 6.5, which mimics CF airway mucus. Killing required a pH lower than 7, implicating formation of nitrous acid (HNO2) and NO, that adds NO equivalents to cellular molecules. Eighty-seven percent of CF isolates possessed mucA mutations and were killed by HNO2 (3-log reduction in 4 days). Furthermore, antibiotic-resistant strains determined were also equally sensitive to HNO2. More importantly, HNO2 killed mucoid bacteria (a) in anaerobic biofilms; (b) in vitro in ultrasupernatants of airway secretions derived from explanted CF patient lungs; and (c) in mouse lungs in vivo in a pH-dependent fashion, with no organisms remaining after daily exposure to HNO2 for 16 days. HNO2 at these levels of acidity and NO2 - also had no adverse effects on cultured human airway epithelia in vitro. In summary, selective killing by HNO2 may provide novel insights into the important clinical goal of eradicating mucoid P. aeruginosa from the CF airways.

Original languageEnglish (US)
Pages (from-to)436-446
Number of pages11
JournalJournal of Clinical Investigation
Volume116
Issue number2
DOIs
StatePublished - Feb 1 2006

ASJC Scopus subject areas

  • Medicine(all)

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    Sang, S. Y., Coakley, R., Lau, G. W., Lymar, S. V., Gaston, B., Karabulut, A. C., Hennigan, R. F., Hwang, S. H., Buettner, G., Schurr, M. J., Mortensen, J. E., Burns, J. L., Speert, D., Boucher, R. C., & Hassett, D. J. (2006). Anaerobic killing of mucoid Pseudomonas aeruginosa by acidified nitrite derivatives under cystic fibrosis airway conditions. Journal of Clinical Investigation, 116(2), 436-446. https://doi.org/10.1172/JCI24684