摘要

随着抗微生物抗性（AMR）威胁的增加，迫切需要提高现有抗生素的功效。了解细菌逃避这些药物的无数机制对于设计针对它们的新策略具有极大的价值。天蓝色链霉菌A3（2）M145属于放线菌属物种，其负责超过三分之二的抗生素。因此，这组细菌编码可以抵抗内源性和非内源性抗生素的各种机制。在早期的一项研究中，我们研究了这些细菌在环境中培养时对环丙沙星的转录组学反应。在这项工作中，我们研究了当细菌在富含营养的培养基中生长时，药物的最低抑制浓度增加四倍的原因。通过转录组学，生物化学和显微镜研究，我们显示S.coelicolor以浓度依赖性方式响应环丙沙星。虽然，亚抑制浓度的药物主要引起氧化应激，但环丙沙星的抑制浓度在细胞中引起更严重的全基因组反应，其范围从熟悉的SOS反应和DNA修复途径的上调到广泛的改变。中枢代谢途径，以适应核苷酸和其他前体的增加需求。此外，肽聚糖合成基因的上调以及显微镜图像表明细胞形态的改变以增加抗生素应激期间细菌的适应性。该数据还指出在富含培养基中培养的细胞中增强的外排活性，其有助于显着降低细胞内药物浓度并因此促进存活。

With the rising threat of anti-microbial resistance (AMR), there is an urgent need to enhance efficacy of existing antibiotics. Understanding the myriad mechanisms through which bacteria evade these drugs would be of immense value to designing novel strategies against them. Streptomyces coelicolor A3(2) M145 belongs to the actinomyctes species that are responsible for more than two-thirds of antibiotics. This group of bacteria therefore encodes for various mechanisms that can resist both endogenous and non-endogenous antibiotics. In an earlier study, we had studied the transcriptomic response of these bacteria to ciprofloxacin, when cultured in a minimal media. In this work, we investigate why the minimum inhibitory concentration of the drug increases by fourfold when the bacteria are grown in a nutrient-rich media. Through transcriptomic, biochemical, and microscopic studies, we show that S. coelicolor responds to ciprofloxacin in a concentration-dependent manner. While, sub-inhibitory concentration of the drug primarily causes oxidative stress, the inhibitory concentration of ciprofloxacin evokes a more severe genome-wide response in the cell, which ranges from the familiar upregulation of the SOS response and DNA repair pathways to the widespread alterations in the central metabolism pathway to accommodate the increased needs of nucleotides and other precursors. Further, the upregulation of peptidoglycan synthesis genes, along with microscopy images, suggest alterations in the cell morphology to increase fitness of the bacteria during the antibiotic stress. The data also points to the enhanced efflux activity in cells cultured in rich media that contributes significantly towards reducing intracellular drug concentration and thus promotes survival.

https://www.ncbi.nlm.nih.gov/pubmed/30327831