Center for Adaptation Genetics and Drug Resistance, Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA.
Antimicrob Agents Chemother. 2010 May;54(5):2125-34. doi: 10.1128/AAC.01420-09. Epub 2010 Mar 8.
Multidrug resistance (MDR) in clinical isolates of Escherichia coli can be associated with overexpression of marA, a transcription factor that upregulates multidrug efflux and downregulates membrane permeability. Using random transposome mutagenesis, we found that many chromosomal genes and environmental stimuli affected MarA-mediated antibiotic resistance. Seven genes affected resistance mediated by MarA in an antibiotic-specific way; these were mostly genes encoding unrelated enzymes, transporters, and unknown proteins. Other genes affected MarA-mediated resistance to all antibiotics tested. These genes were acrA, acrB, and tolC (which encode the major MarA-regulated multidrug efflux pump AcrAB-TolC), crp, cyaA, hns, and pcnB (four genes involved in global regulation of gene expression), and the unknown gene damX. The last five genes affected MarA-mediated MDR by altering marA expression or MarA function specifically on acrA. These findings demonstrate that MarA-mediated MDR is regulated at multiple levels by different genes and stimuli, which makes it both complex and fine-tuned and interconnects it with global cell regulation and metabolism. Such a regulation could contribute to the adaptation and spread of MDR strains and may be targeted to treat antibiotic-resistant E. coli and related pathogens.
临床分离大肠埃希菌的多药耐药性（MDR）可能与 marA 的过度表达有关，marA 是一种转录因子，可上调多种药物外排并下调膜通透性。使用随机转座子诱变，我们发现许多染色体基因和环境刺激因素影响 MarA 介导的抗生素耐药性。有七个基因以抗生素特异性的方式影响 MarA 介导的耐药性；这些基因大多编码不相关的酶、转运蛋白和未知蛋白。其他基因影响 MarA 介导的所有抗生素的耐药性。这些基因是 acrA、acrB 和 tolC（编码主要的 MarA 调控的多药外排泵 AcrAB-TolC）、crp、cyaA、hns 和 pcnB（参与基因表达全局调控的四个基因）和未知基因 damX。最后五个基因通过改变 marA 表达或专门在 acrA 上改变 MarA 功能来影响 MarA 介导的 MDR。这些发现表明，MarA 介导的 MDR 受到不同基因和刺激因素的多层次调节，使其既复杂又精细，并与全局细胞调节和代谢相连接。这种调节可能有助于 MDR 菌株的适应和传播，并可能成为治疗抗生素耐药性大肠埃希菌和相关病原体的靶点。
