Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis.
Low-Dose Nitric Oxide as Targeted Anti-biofilm Adjunctive Therapy to Treat Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis.
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DOI：
10.1016/j.ymthe.2017.06.021
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发表时间：
2017-09-06
期刊：
影响因子：
--
通讯作者：
Webb JS
中科院分区：
文献类型：
--
作者：
Howlin RP;Cathie K;Hall-Stoodley L;Cornelius V;Duignan C;Allan RN;Fernandez BO;Barraud N;Bruce KD;Jefferies J;Kelso M;Kjelleberg S;Rice SA;Rogers GB;Pink S;Smith C;Sukhtankar PS;Salib R;Legg J;Carroll M;Daniels T;Feelisch M;Stoodley P;Clarke SC;Connett G;Faust SN;Webb JS
尽管积极的抗生素治疗，铜绿假单胞菌的支气管肺定植导致囊性纤维化（CF）的持续发病率和死亡率。CF肺中的慢性铜绿假单胞菌感染与被称为生物膜的结构化的、耐抗生素的细菌聚集体相关。我们已经在离体模型和概念验证双盲临床试验中证明了非杀菌、低剂量一氧化氮（NO）（一种诱导生物膜分散的信号分子）作为CF中铜绿假单胞菌生物膜感染的新型连续疗法的作用。亚微摩尔NO浓度单独引起破坏的生物膜内的离体CF痰和统计学显着降低离体生物膜耐受妥布霉素和妥布霉素联合头孢他啶。在12名患者的随机临床试验中，在7天的治疗期间，与安慰剂相比，吸入10 ppm NO导致铜绿假单胞菌生物膜聚集体显著减少。我们的研究结果表明，使用低剂量的NO作为连续治疗，以提高用于治疗急性铜绿假单胞菌加重CF的抗生素的疗效的好处。诱导生物膜破坏的策略有可能克服CF和其他生物膜相关疾病中的生物膜相关抗生素耐受性。本文报道了人类疾病中靶向抗生物膜治疗的第一个例子。我们已经证明，使用低剂量的一氧化氮作为非杀菌信号分子，以诱导生物膜分散可能是有用的，作为一种新的连续治疗，以治疗慢性假单胞菌生物膜感染囊性纤维化。
Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases. This paper reports the first example of targeted anti-biofilm therapy in human disease. We have demonstrated that using low-dose nitric oxide as a non-bactericidal signaling molecule to induce biofilm dispersal may be useful as a novel adjunctive therapy to treat chronic pseudomonal biofilm infection in cystic fibrosis.
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影响因子：
5.7
作者：
Barraud N;Storey MV;Moore ZP;Webb JS;Rice SA;Kjelleberg S
通讯作者：
Kjelleberg S
影响因子：
14
作者：
Hetrick, Evan M.;Shin, Jae Ho;Paul, Heather S.;Schoenfisch, Mark H.
通讯作者：
Schoenfisch, Mark H.
影响因子：
3.7
作者：
Conibear TC;Collins SL;Webb JS
通讯作者：
Webb JS
DOI：
10.1016/j.jcf.2005.05.008
发表时间：
2005-08-01
期刊：
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
影响因子：
--
作者：
de Winter-de Groot, Karin M;van der Ent, Cornelis K
通讯作者：
van der Ent, Cornelis K
影响因子：
17.1
作者：
Hetrick, Evan M.;Shin, Jae Ho;Schoenfisch, Mark H.
通讯作者：
Schoenfisch, Mark H.