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

被引:181
作者
Yoon, SS
Coakley, R
Lau, GW
Lymar, SV
Gaston, B
Karabulut, AC
Hennigan, RF
Hwang, SH
Buettner, G
Schurr, MJ
Mortensen, JE
Burns, JL
Speert, D
Boucher, RC
Hassett, DJ
机构
[1] Univ Cincinnati, Coll Med, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA
[2] Univ N Carolina, Cyst Fibrosis Pulm Res & Treatment Ctr, Chapel Hill, NC USA
[3] Univ N Carolina, Dept Pulm Biol, Chapel Hill, NC USA
[4] Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA
[5] Univ Cincinnati, Coll Med, Dept Cell Biol, Cincinnati, OH 45267 USA
[6] Univ Virginia, Sch Med, Dept Pediat Crit Care, Charlottesville, VA 22908 USA
[7] Mt Sinai Sch Med, Dept Pharmacol & Biol Chem, New York, NY USA
[8] Univ Iowa, Dept Chem, Iowa City, IA 52242 USA
[9] Tulane Univ, Dept Microbiol, New Orleans, LA 70118 USA
[10] Childrens Hosp, Dept Pediat Pathol & Lab Med, Cincinnati, OH 45229 USA
[11] Childrens Hosp & Reg Med Ctr, Infect Dis Sect, Seattle, WA USA
[12] Univ British Columbia, Dept Pediat, Vancouver, BC V6T 1W5, Canada
关键词
D O I
10.1172/JCI24684
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:436 / 446
页数:11
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