The complex development of psoralen-interstrand crosslink resistance in Escherichia coli requires AcrR inactivation, retention of a marbox sequence, and one of three MarA, SoxS, or Rob global regulators

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2025-01-01 DOI:10.1016/j.mrfmmm.2025.111898

Travis K. Worley , Ayah H. Asal, Lo Cooper, Charmain T. Courcelle, Justin Courcelle

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引用次数: 0

Abstract

Crosslinking agents, such as psoralen and UVA radiation, can be effectively used as antimicrobials and for treating several dysplastic conditions in humans, including some cancers. Yet, both cancer cells and bacteria can become resistant to these compounds, making it important to understand how resistance develops. Recently, several mutants were isolated that developed high levels of resistance to these compounds through upregulation of components of the AcrAB-TolC efflux pump. Here, we characterized these mutants and found that resistance specifically requires inactivating mutations of the acrR transcriptional repressor which also retain the marbox sequence found within this coding region. In addition, the presence of any one of three global regulators, MarA, SoxS, or Rob, is necessary and sufficient to bind to the marbox sequence and activate resistance. Notably, although psoralen is a substrate for the efflux pump, these regulators are not naturally responsive to this stress as neither psoralen, UVA, nor crosslink induction upregulates acrAB expression in the absence of mutation.

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在大肠杆菌中，补骨脂素-链间交联抗性的复杂发展需要AcrR失活、marbox序列的保留以及三种MarA、SoxS或Rob全球调控因子中的一种

交联剂，如补骨脂素和UVA辐射，可以有效地用作抗菌剂和治疗人类的几种发育不良疾病，包括一些癌症。然而，癌细胞和细菌都可能对这些化合物产生耐药性，因此了解耐药性是如何产生的非常重要。最近，一些突变体被分离出来，它们通过上调acrabb - tolc外排泵的成分，对这些化合物产生了高水平的抗性。在这里，我们对这些突变体进行了表征，并发现抗性特异性地需要acrR转录抑制因子的失活突变，这些突变也保留了该编码区域内发现的marbox序列。此外，三种全局调控因子（MarA、SoxS或Rob）中的任何一种的存在都是与marbox序列结合并激活抗性的必要和充分条件。值得注意的是，尽管补骨脂素是外排泵的底物，但这些调节因子对这种应激没有自然反应，因为补骨脂素、UVA和交联诱导都不能在没有突变的情况下上调acrAB的表达。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.