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

Authors
 Sang Sun Yoon  ;  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 
Citation
 JOURNAL OF CLINICAL INVESTIGATION, Vol.116(2) : 436-446, 2006 
Journal Title
JOURNAL OF CLINICAL INVESTIGATION
ISSN
 0021-9738 
Issue Date
2006
MeSH
Anaerobiosis ; Animals ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Biofilms ; Cells, Cultured ; Child ; Child, Preschool ; Cystic Fibrosis/metabolism* ; Cystic Fibrosis/microbiology ; Drug Resistance, Bacterial* ; Epithelial Cells/cytology ; Humans ; Hydrogen-Ion Concentration ; Infant ; Mice ; Microbial Sensitivity Tests ; Mucus/chemistry ; Nitrites/metabolism* ; Pseudomonas Infections ; Pseudomonas aeruginosa/genetics ; Pseudomonas aeruginosa/metabolism* ; Respiratory Mucosa/cytology ; Sputum/chemistry ; Sputum/microbiology
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.
Files in This Item:
T200604859.pdf Download
DOI
10.1172/JCI24684
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Yoon, Sang Sun(윤상선) ORCID logo https://orcid.org/0000-0003-2979-365X
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/111062
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