Agmatine accumulation by Pseudomonas aeruginosa clinical isolates confers antibiotic tolerance and dampens host inflammation
Agmatine accumulation by Pseudomonas aeruginosa clinical isolates confers antibiotic tolerance and dampens host inflammation
复制标题
DOI：
10.1099/jmm.0.000928
复制
发表时间：
2019-03-01
影响因子：
3
通讯作者：
Hunter, Ryan C.
中科院分区：
文献类型：
--
作者：
McCurtain, Jennifer L.;Gilbertsen, Adam J.;Hunter, Ryan C.
目的.在囊性纤维化（CF）气道中，铜绿假单胞菌响应于炎症、抗生素压力、氧化应激和动态生物可利用的营养库而经历多种生理变化。这些包括导致毒性降低的功能丧失突变、代谢改变和其他被认为赋予长期持久性选择优势的表型。最近，从CF患者中培养出大量产生胍丁胺（脱羧精氨酸）的铜绿假单胞菌临床分离株。这种代谢物的痰液浓度也显示与疾病严重程度相关。这就提出了一个问题，胍丁胺的积累是否也可能赋予铜绿假单胞菌在肺部慢性定植的选择性优势。我们筛选了铜绿假单胞菌CF临床分离株的文库，发现近似5%的受试者携带具有胍丁胺高产表型的分离株。胍丁胺积累是aguA突变的直接结果，aguA编码精氨酸脱亚胺酶，催化胍丁胺转化为各种多胺。我们还发现，胍丁胺高产菌株（aguA-）增加了耐阳离子抗生素庆大霉素，妥布霉素和粘菌素相对于他们的染色体互补菌株（aguA+）。最后，我们揭示了胍丁胺减少气道上皮细胞对细菌感染的反应产生IL-8，从而减少急性肺炎模型中小鼠气道中性粒细胞的募集。这些数据强调了细菌衍生的胍丁胺的潜在新作用，可能对CF气道中铜绿假单胞菌的长期持续存在产生重要影响。
Purpose. In the cystic fibrosis (CF) airways, Pseudomonas aeruginosa undergoes diverse physiological changes in response to inflammation, antibiotic pressure, oxidative stress and a dynamic bioavailable nutrient pool. These include loss-of-function mutations that result in reduced virulence, altered metabolism and other phenotypes that are thought to confer a selective advantage for long-term persistence. Recently, clinical isolates of P aeruginosa that hyperproduce agmatine (decarboxylated arginine) were cultured from individuals with CF. Sputum concentrations of this metabolite were also shown to correlate with disease severity. This raised the question of whether agmatine accumulation might also confer a selective advantage for P aeruginosa during chronic colonization of the lung.Methodology and Results. We screened a library of P aeruginosa CF clinical isolates and found that similar to 5% of subjects harboured isolates with an agmatine hyperproducing phenotype. Agmatine accumulation was a direct result of mutations in aguA, encoding the arginine deiminase that catalyses the conversion of agmatine into various polyamines. We also found that agmatine hyperproducing isolates (aguA-) had increased tolerance to the cationic antibiotics gentamicin, tobramycin and colistin relative to their chromosomally complemented strains (aguA+). Finally, we revealed that agmatine diminishes IL-8 production by airway epithelial cells in response to bacterial infection, with a consequent decrease in neutrophil recruitment to the murine airways in an acute pneumonia model.Conclusion. These data highlight a potential new role for bacterial-derived agmatine that may have important consequences for the long-term persistence of P. aeruginosa in the CF airways.