Zemke Anna C, Gladwin Mark T, Bomberger Jennifer M
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Antimicrob Agents Chemother. 2015;59(6):3329-34. doi: 10.1128/AAC.00546-15. Epub 2015 Mar 23.
Sodium nitrite has broad antimicrobial activity at pH 6.5, including the ability to prevent biofilm growth by Pseudomonas aeruginosa on the surfaces of airway epithelial cells. Because of its antimicrobial activity, nitrite is being investigated as an inhaled agent for chronic P. aeruginosa airway infections in cystic fibrosis patients. However, the interaction between nitrite and commonly used aminoglycosides is unknown. This paper investigates the interaction between nitrite and tobramycin in liquid culture, abiotic biofilms, and a biotic biofilm model simulating the conditions in the cystic fibrosis airway. The addition of nitrite prevented killing by aminoglycosides in liquid culture, with dose dependence between 1.5 and 15 mM. The effect was not blocked by the nitric oxide scavenger CPTIO or dependent on efflux pump activity. Nitrite shifted the biofilm minimal bactericidal concentration (MBC-biofilm) from 256 μg/ml to >1,024 μg/ml in an abiotic biofilm model. In a biotic biofilm model, the addition of 50 mM nitrite decreased the antibiofilm activity of tobramycin by up to 1.2 log. Respiratory chain inhibition recapitulated the inhibition of aminoglycoside activity by nitrite, suggesting a potential mechanism of inhibition of energy-dependent aminoglycoside uptake. In summary, sodium nitrite induces resistance to both gentamicin and tobramycin in P. aeruginosa grown in liquid culture, as an abiotic biofilm, or as a biotic biofilm.
亚硝酸钠在pH 6.5时具有广泛的抗菌活性，包括能够阻止铜绿假单胞菌在气道上皮细胞表面形成生物膜。由于其抗菌活性，亚硝酸盐正在作为一种吸入剂用于研究囊性纤维化患者慢性铜绿假单胞菌气道感染。然而，亚硝酸盐与常用氨基糖苷类药物之间的相互作用尚不清楚。本文研究了亚硝酸盐与妥布霉素在液体培养、非生物膜以及模拟囊性纤维化气道条件的生物膜模型中的相互作用。在液体培养中，添加亚硝酸盐可防止氨基糖苷类药物的杀菌作用，在1.5至15 mM之间存在剂量依赖性。一氧化氮清除剂CPTIO并未阻断该效应，且该效应不依赖于外排泵活性。在非生物膜模型中，亚硝酸盐使生物膜最低杀菌浓度（MBC-生物膜）从256 μg/ml变为>1024 μg/ml。在生物膜模型中，添加50 mM亚硝酸盐可使妥布霉素的抗生物膜活性降低多达1.2个对数。呼吸链抑制重现了亚硝酸盐对氨基糖苷类药物活性的抑制作用，提示了抑制能量依赖性氨基糖苷类药物摄取的潜在机制。总之，亚硝酸钠可诱导在液体培养、非生物膜或生物膜中生长的铜绿假单胞菌对庆大霉素和妥布霉素产生耐药性。
