Anaerobic killing of mucoid Pseudomonas aeruginosa by acidified nitrite derivatives under cystic fibrosis airway conditions.
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.
Yoon
Sang Sun
SS
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
Coakley
Ray
R
Lau
Gee W
GW
Lymar
Sergei V
SV
Gaston
Benjamin
B
Karabulut
Ahmet C
AC
Hennigan
Robert F
RF
Hwang
Sung-Hei
SH
Buettner
Garry
G
Schurr
Michael J
MJ
Mortensen
Joel E
JE
Burns
Jane L
JL
Speert
David
D
Boucher
Richard C
RC
Hassett
Daniel J
DJ
D000693:Anaerobiosis; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D018441:Biofilms; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000378:metabolism* / Q000382:microbiology; D024881:Drug Resistance, Bacterial; D004847:Epithelial Cells / Q000166:cytology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007223:Infant; D051379:Mice; D008826:Microbial Sensitivity Tests; D009093:Mucus / Q000737:chemistry; D009573:Nitrites / Q000378:metabolism*; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology; D013183:Sputum / Q000737:chemistry / Q000382:microbiology
D001426:Bacterial Proteins; C107895:MucA protein, Pseudomonas; D009573:Nitrites