铜绿假单胞菌内在耐药性相关基因的筛选及研究
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摘要
二十世纪五十年代后,由于持续不合理的使用抗生素,临床细菌的耐药性现在已经成为全球感染领域引人瞩目的问题之一。铜绿假单胞菌(Pseudomonas aeruginosa)是一种革兰氏阴性条件致病菌,主要在临床中引起一定程度的感染。由于铜绿假单胞菌自身的特点：如细胞本身对抗生素的通透性低,形成生物被膜等,赋予了铜绿假单胞菌特有的内在抗药性。正是由于铜绿假单胞菌抗药性的出现,使得对于铜绿假单胞菌感染的治疗变得非常的棘手。因此,对于铜绿假单胞菌内在抗药性的研究就变得至关重要。
为了寻找铜绿假单胞菌中与抗生素抗性相关的基因,我们构建了含有17000多个克隆的随机转座突变体库,并用不同类型的七种抗生素对转座突变体库进行了筛选。首先,在含有最小抑制浓度(Minimal Inhibitors Concentration, MIC)的固体平板上生长的转座突变体,被认为是抗性转座突变体。在1/2最小抑制浓度(MIC)的固体平板上不能生长的转座突变体被认为是敏感转座突变体。然后对固体平板筛选出来的转座突变体在液体培养基中重新进行一次筛选,并且确定每个转座突变体各自的最小抑制浓度(MIC)。最终通过随机PCR、测序和比对,确定了转座突变体库中的43个转座突变体的突变位点(即43个基因)。这些转座突变体与野生型的铜绿假单胞菌相比较至少对一种抗生素的敏感程度发生了3倍或者3倍以上的变化。还有一些转座突变体对三种抗生素都有3倍以上的变化,比如：PA4024、PA4342和PA4456的转座突变体。有两个转座突变体对羧苄青霉素的抗性提高了128倍。在这43个基因当中,现已经报道的与抗生素有关的基因有三个,他们是PA0424(编码多重耐药操纵子的抑制蛋白MexR)、PA0426(编码与抗生素抗性相关的RND外排泵的蛋白MexB; Resistance-Nodulation-Cell Division)和PA4207(编码与抗生素抗性相关的RND外排泵的蛋白)。而其它基因并未见其与抗生素抗性有关的报道。
铜绿假单胞菌中被预测为ABC转运器的蛋白很多。现在已经清楚的知道ATP依赖的ABC转运器在生物体中具有非常重要的作用。在我们筛选得到的结果中,PA4456被预测可能是ATP依赖的ABC转运器的组成部分,为了进一步确定其基因的功能,我们对其进行了深入的研究,如抗生素敏感性的测定,荧光分光光度法测定了细胞内四环素的积累等。结果表明：(1)PA4456基因在细胞对四环素和有机溶剂的转运过程具有重要的功能；(2)PA4456突变体对氯霉素(Chloramphenicol)、氨甲氧嘧啶(Trimethoprim)、环丙沙星(Ciprofloxacin)、二甲苯(Xylene)、二甲基甲酰胺(Dimethy- formamide)和甲苯(Toluene)的敏感性增加。
为了了解其基因功能的调控机理,我们通过随机转座突变的方法从整个基因组水平筛选对PA4456具有调节作用的基因,最终我们发现PA 1180 (phoQ)对PA4456具有潜在的抑制调节作用,在phoQ突变体中,PA4456的表达增加了8倍之多。
总而言之,细菌抗性的出现是细菌本身改变自身调控网络的结果。而我们筛选得到的数据表明,在铜绿假单胞菌基因组当中,许多未知功能的基因或者参与细菌代谢和调控网络中的基因对细菌的耐药性都有着非常重要的作用。
The issue of antibiotic resistance has received considerable attention due to the problem of the emergence and rapid expansion of antibiotic-resistant pathogenic bacteria. Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative opportunistic pathogen that continues to be a major cause of opportunistic nosocomial infections. It is also the important cause of chronic lung infections contributing to the death of patients with cystic fibrosis. One of the most important reasons for its prominence as a pathogen is that P. aeruginosa has high intrinsic resistance characteristics to many antibiotics. It is important to study insights into the mechanisms of resistance and develop new approaches to combat resistance of P. aeruginosa.
To find such genes, a P. aeruginosa transposon insertion library of c.a.17000 clones was constructed and screened for resistant and hyper-sensitive mutants using seven antibiotics. The screen was initially carried out on agar plates containing different concentrations of these antibiotics. Colonies grown at MIC were collected as the resistant mutants, and those unable to grow at 1/2 MIC were considered hyper-susceptible mutants. Further tests were done in liquid medium with series of antibiotic concentrations and the exact MICs of these mutants were defined. Transposon insertions in 43 genes were found to cause a 3-fold or higher hypersusceptibility to at least one antibiotic. Some of the mutants exhibited at least threefold change in susceptibility to three antibiotics; they are mutants in PA4024, PA4342, and PA4456. Two mutants increased the bacterial resistance to carbenicillin by 128-fold. Among the disrupted genes identified in the mutants, two genes PA0426, PA4207 which encodes a Resistance-Nodulation-Cell Division multidrug efflux transporter and another one PA0424 which encodes multidrug resistance operon repressor MexR have an apparent role in P. aeruginosa resistance. Others show less obvious involvement in antibiotic resistance. The results indicate many genes previously unknown to be involved in antibiotic resistance are important for the intrinsic antibiotic resistance in P. aeruginosa, suggesting mechanisms other than membrane permeability and efflux pump play important roles in bacterial resistance to antibiotics. These mechanisms may be exploited as new antibiotic targets.
ABC transporters are widespread among P. aeruginosa and comprise one of the largest protein families. It is clear that ATP-binding cassette (ABC) transporters play an important role in bacteria and living organisms. In order to find new target to eliminate the antibiotic resistance, we identified and characterized a mutant PA4456 encoding a putative ATP-binding component of ABC transporter essential for the PAO intrinsic resistance. Furthermore, the mutant deficient in this putative ATP binding component was analyzed. Conclusions withdrawn from the results were:(1) higher sensitive to tetracycline and greater accumulation of tetracycline compared to the WT using the florescence technique. (2) also sensitive to chloramphenicol, trimethoprim, ciprofloxacin, xylene, dimethy-formamide, and toluene. Complementation analyses indicated that PA4456 is important for the putative operon to involve in antibiotics transporter. These results strongly suggested that the predicted ATP-binding component (PA4456) is involved in antibiotic and organic transporter.
In order to find out the network of genes, a genome-wide search of regulators for the transporter operon identified PhoQ as a potential repressor. More than 8-fold increase of PA4456 expression was observed in a phoQ mutant. These results indicate that this putative ABC transporter is functionally active in P. aeruginosa and regulated by the two component system of PhoQ.
It has already been show that antibiotic resistance can produce specific bacterial ways of life and changes in bacterial metabolism. It is thus conceivable that resistance has integrated into global regulatory networks and might be controlled by the metabolic condition of bacteria.
为了寻找铜绿假单胞菌中与抗生素抗性相关的基因,我们构建了含有17000多个克隆的随机转座突变体库,并用不同类型的七种抗生素对转座突变体库进行了筛选。首先,在含有最小抑制浓度(Minimal Inhibitors Concentration, MIC)的固体平板上生长的转座突变体,被认为是抗性转座突变体。在1/2最小抑制浓度(MIC)的固体平板上不能生长的转座突变体被认为是敏感转座突变体。然后对固体平板筛选出来的转座突变体在液体培养基中重新进行一次筛选,并且确定每个转座突变体各自的最小抑制浓度(MIC)。最终通过随机PCR、测序和比对,确定了转座突变体库中的43个转座突变体的突变位点(即43个基因)。这些转座突变体与野生型的铜绿假单胞菌相比较至少对一种抗生素的敏感程度发生了3倍或者3倍以上的变化。还有一些转座突变体对三种抗生素都有3倍以上的变化,比如：PA4024、PA4342和PA4456的转座突变体。有两个转座突变体对羧苄青霉素的抗性提高了128倍。在这43个基因当中,现已经报道的与抗生素有关的基因有三个,他们是PA0424(编码多重耐药操纵子的抑制蛋白MexR)、PA0426(编码与抗生素抗性相关的RND外排泵的蛋白MexB; Resistance-Nodulation-Cell Division)和PA4207(编码与抗生素抗性相关的RND外排泵的蛋白)。而其它基因并未见其与抗生素抗性有关的报道。
铜绿假单胞菌中被预测为ABC转运器的蛋白很多。现在已经清楚的知道ATP依赖的ABC转运器在生物体中具有非常重要的作用。在我们筛选得到的结果中,PA4456被预测可能是ATP依赖的ABC转运器的组成部分,为了进一步确定其基因的功能,我们对其进行了深入的研究,如抗生素敏感性的测定,荧光分光光度法测定了细胞内四环素的积累等。结果表明：(1)PA4456基因在细胞对四环素和有机溶剂的转运过程具有重要的功能；(2)PA4456突变体对氯霉素(Chloramphenicol)、氨甲氧嘧啶(Trimethoprim)、环丙沙星(Ciprofloxacin)、二甲苯(Xylene)、二甲基甲酰胺(Dimethy- formamide)和甲苯(Toluene)的敏感性增加。
为了了解其基因功能的调控机理,我们通过随机转座突变的方法从整个基因组水平筛选对PA4456具有调节作用的基因,最终我们发现PA 1180 (phoQ)对PA4456具有潜在的抑制调节作用,在phoQ突变体中,PA4456的表达增加了8倍之多。
总而言之,细菌抗性的出现是细菌本身改变自身调控网络的结果。而我们筛选得到的数据表明,在铜绿假单胞菌基因组当中,许多未知功能的基因或者参与细菌代谢和调控网络中的基因对细菌的耐药性都有着非常重要的作用。
The issue of antibiotic resistance has received considerable attention due to the problem of the emergence and rapid expansion of antibiotic-resistant pathogenic bacteria. Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative opportunistic pathogen that continues to be a major cause of opportunistic nosocomial infections. It is also the important cause of chronic lung infections contributing to the death of patients with cystic fibrosis. One of the most important reasons for its prominence as a pathogen is that P. aeruginosa has high intrinsic resistance characteristics to many antibiotics. It is important to study insights into the mechanisms of resistance and develop new approaches to combat resistance of P. aeruginosa.
To find such genes, a P. aeruginosa transposon insertion library of c.a.17000 clones was constructed and screened for resistant and hyper-sensitive mutants using seven antibiotics. The screen was initially carried out on agar plates containing different concentrations of these antibiotics. Colonies grown at MIC were collected as the resistant mutants, and those unable to grow at 1/2 MIC were considered hyper-susceptible mutants. Further tests were done in liquid medium with series of antibiotic concentrations and the exact MICs of these mutants were defined. Transposon insertions in 43 genes were found to cause a 3-fold or higher hypersusceptibility to at least one antibiotic. Some of the mutants exhibited at least threefold change in susceptibility to three antibiotics; they are mutants in PA4024, PA4342, and PA4456. Two mutants increased the bacterial resistance to carbenicillin by 128-fold. Among the disrupted genes identified in the mutants, two genes PA0426, PA4207 which encodes a Resistance-Nodulation-Cell Division multidrug efflux transporter and another one PA0424 which encodes multidrug resistance operon repressor MexR have an apparent role in P. aeruginosa resistance. Others show less obvious involvement in antibiotic resistance. The results indicate many genes previously unknown to be involved in antibiotic resistance are important for the intrinsic antibiotic resistance in P. aeruginosa, suggesting mechanisms other than membrane permeability and efflux pump play important roles in bacterial resistance to antibiotics. These mechanisms may be exploited as new antibiotic targets.
ABC transporters are widespread among P. aeruginosa and comprise one of the largest protein families. It is clear that ATP-binding cassette (ABC) transporters play an important role in bacteria and living organisms. In order to find new target to eliminate the antibiotic resistance, we identified and characterized a mutant PA4456 encoding a putative ATP-binding component of ABC transporter essential for the PAO intrinsic resistance. Furthermore, the mutant deficient in this putative ATP binding component was analyzed. Conclusions withdrawn from the results were:(1) higher sensitive to tetracycline and greater accumulation of tetracycline compared to the WT using the florescence technique. (2) also sensitive to chloramphenicol, trimethoprim, ciprofloxacin, xylene, dimethy-formamide, and toluene. Complementation analyses indicated that PA4456 is important for the putative operon to involve in antibiotics transporter. These results strongly suggested that the predicted ATP-binding component (PA4456) is involved in antibiotic and organic transporter.
In order to find out the network of genes, a genome-wide search of regulators for the transporter operon identified PhoQ as a potential repressor. More than 8-fold increase of PA4456 expression was observed in a phoQ mutant. These results indicate that this putative ABC transporter is functionally active in P. aeruginosa and regulated by the two component system of PhoQ.
It has already been show that antibiotic resistance can produce specific bacterial ways of life and changes in bacterial metabolism. It is thus conceivable that resistance has integrated into global regulatory networks and might be controlled by the metabolic condition of bacteria.
引文
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