Prickett Michelle H, Hauser Alan R, McColley Susanna A, Cullina Joanne, Potter Eileen, Powers Cathy, Jain Manu
Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
Thorax. 2017 Jan;72(1):40-47. doi: 10.1136/thoraxjnl-2015-208027. Epub 2016 Jun 20.
Aminoglycoside (AG) resistance of Pseudomonas aeruginosa in cystic fibrosis (CF) is associated with poorer clinical outcomes and is usually due to overexpression of the efflux pump MexXY. MexXY is regulated by mexZ, one of the most commonly mutated genes in CF P. aeruginosa isolates. Little is known about the evolutionary relationship between AG resistance, MexXY expression and mexZ mutations.
To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations.
CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children and children with new infection.
One P. aeruginosa isolate from each patient was analysed for mexZ mutations, mexY mRNA expression and amikacin resistance.
56 patients with CF were enrolled: 21 children with new P. aeruginosa infection, 18 CI children and 17 CI adults. Amikacin resistance and mexY mRNA expression were higher in cohorts with longer P. aeruginosa infection. The prevalence of non-conservative mexZ mutations was 0%, 33% and 65% in children with new infection, CI children and CI adults, respectively. The same trend was seen in the ratio of non-conservative to non-synonymous mexZ mutations. Of isolates with non-conservative mexZ mutations, 59% were amikacin-resistant compared with 18% of isolates with non-synonymous mutations. The doubling rate of amikacin resistance and non-conservative mexZ mutations was approximately 5 years.
P. aeruginosa mexZ mutations undergo positive selection resulting in increased mexY mRNA expression and amikacin resistance and likely play a role in bacterial adaption in the CF lung.
囊性纤维化（CF）患者中，铜绿假单胞菌对氨基糖苷类药物（AG）的耐药性与较差的临床预后相关，通常是由于外排泵MexXY的过度表达所致。MexXY由mexZ调控，mexZ是CF铜绿假单胞菌分离株中最常发生突变的基因之一。关于AG耐药性、MexXY表达和mexZ突变之间的进化关系，目前所知甚少。
检验铜绿假单胞菌对AG的耐药性与较高的MexXY表达和mexZ突变同时发生这一假设。
比较CF铜绿假单胞菌在慢性感染（CI）成人、CI儿童和新发感染儿童中的分离株。
分析每位患者的一株铜绿假单胞菌分离株的mexZ突变、mexY mRNA表达和阿米卡星耐药性。
纳入56例CF患者，其中21例新发铜绿假单胞菌感染儿童、18例CI儿童和17例CI成人。铜绿假单胞菌感染时间较长的队列中，阿米卡星耐药性和mexY mRNA表达较高。新发感染儿童、CI儿童和CI成人中，非保守性mexZ突变的发生率分别为0%、33%和65%。非保守性与非同义mexZ突变的比例也呈现相同趋势。在具有非保守性mexZ突变的分离株中，59%对阿米卡星耐药，而具有非同义突变的分离株中这一比例为18%。阿米卡星耐药性和非保守性mexZ突变的倍增时间约为5年。
铜绿假单胞菌mexZ突变经历正选择，导致mexY mRNA表达增加和阿米卡星耐药性增强，可能在CF肺部细菌适应过程中发挥作用。
