The anaerobic pathogen Clostridium difficile is of growing significance for the health care system due to its increasing incidence and mortality. As C. difficile infection is both supported and treated by antibiotics, a deeper knowledge on how antimicrobial agents affect the physiology of this important pathogen may help to understand and prevent the development and spreading of antibiotic resistant strains. As the proteomic response of a cell to stress aims at counteracting the harmful effects of this stress, it can be expected that the pattern of a pathogen's responses to antibiotic treatment will be dependent on the antibiotic mechanism of action. Hence, every antibiotic treatment is expected to result in a specific proteomic signature characterizing its mode of action. In the study presented here, the proteomic response of C. difficile 630∆erm to vancomycin, metronidazole, and fidaxomicin stress was investigated on the level of protein abundance and protein synthesis based on 2D PAGE. The quantification of 425 proteins of C. difficile allowed the deduction of proteomic signatures specific for each drug treatment. Indeed, these proteomic signatures indicate very specific cellular responses to each antibiotic with only little overlap of the responses. Whereas signature proteins for vancomycin stress fulfil various cellular functions, the proteomic signature of metronidazole stress is characterized by alterations of proteins involved in protein biosynthesis and protein degradation as well as in DNA replication, recombination, and repair. In contrast, proteins differentially expressed after fidaxomicin treatment can be assigned to amino acid biosynthesis, transcription, cell motility, and the cell envelope functions. Notably, the data provided by this study hint also at so far unknown antibiotic detoxification mechanisms.

译文

厌氧性病原体艰难梭菌由于其发病率和死亡率不断上升,对医疗保健系统具有日益重要的意义。由于难辨梭状芽胞杆菌感染既受抗生素支持也受其治疗,因此有关抗菌药物如何影响这种重要病原体生理的更深入的知识可能有助于理解和预防抗生素抗性菌株的产生和传播。由于细胞对应激的蛋白质组反应旨在抵消这种应激的有害影响,因此可以预期,病原体对抗生素治疗的反应方式将取决于抗生素的作用机理。因此,预期每种抗生素治疗均会产生表征其作用方式的特定蛋白质组学特征。在此处提出的研究中,基于2D PAGE,研究了艰难梭菌630∆erm对万古霉素,甲硝唑和非达索霉素胁迫的蛋白质组学反应。艰难梭菌425种蛋白质的定量分析可以推断出每种药物治疗特异的蛋白质组学特征。确实,这些蛋白质组学特征表明对每种抗生素的细胞反应非常特异性,而反应却几乎没有重叠。万古霉素应激的特征蛋白具有多种细胞功能,而甲硝唑应激的蛋白质组学特征在于蛋白质生物合成和蛋白质降解以及DNA复制,重组和修复中涉及的蛋白质改变。相反,在非达索霉素处理后差异表达的蛋白质可被分配给氨基酸生物合成,转录,细胞运动性和细胞包膜功能。值得注意的是,这项研究提供的数据也暗示了迄今为止未知的抗生素排毒机制。

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