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首页> 外文学位 >Macrolide and ketolide-based induction of erythromycin resistance methylase type-C in Escherichia coli.
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Macrolide and ketolide-based induction of erythromycin resistance methylase type-C in Escherichia coli.

机译：基于大环内酯和酮内酯的大肠杆菌红霉素抗性甲基化酶C型诱导。

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摘要

Ketolide antibiotics have been labeled as non-inducers of erm -type resistance methylases. In this work we developed a colorimetric erm reporter construct pERMZalpha that was used to identify macrolide and ketolide antibiotics that can induce erm expression. We verified that cladinose-containing macrolides are active in inducing erm expression. We also saw induction of our reporter with various ketolides such as telithromycin and cethromycin. This is in contrast to reports in literature that classify ketolides as non-inducers. The reporter responses were confirmed in the erm system using primer extension analysis. We have concluded that ketolides can induce erm expression, albeit at a slower rate and within a tighter range of drug concentrations than with macrolides such as erythromycin. We also investigated the effect of sequence alterations in the nascent erm leader peptide. We developed two reporter variants with truncated leader sequences. These constructs showed enhanced induction with ketolides while macrolide induction was eliminated. We concluded that minor alterations in the length or sequence of the erm leader can affect the ability of a particular drug to act as an inducer. If this were to happen clinically, a cell that harbored both a traditional version of inducible erm as well as the ketolide-inducible variant would develop resistance to all MLS B drugs when treated with a macrolide or a ketolide drug.; Overall, the impact of this work is three-fold. The reporter system we developed can be used for studying various aspects of the induction of erm expression and for the investigation of the molecular mechanisms of drug-dependent ribosome stalling. Second, we have presented evidence that "non-inducing" drugs like ketolides can in fact induce expression of the inducible erm genes. Therefore, inappropriate antibiotic therapy employing prolonged treatment with low doses of ketolides is expected to result in the development of resistance. Third, we showed that alteration of the erm leader peptide sequence affects the spectrum of antibiotics capable of inducing erm-based resistance. We anticipate that broad clinical use of ketolides will select for erm variants that can be induced by ketolide antibiotics.
机译：酮内酯抗生素已被标记为erm型抗性甲基化酶的非诱导剂。在这项工作中，我们开发了比色erm报告基因构建体pERMZalpha，用于鉴定可以诱导erm表达的大环内酯和酮内酯抗生素。我们验证了含有cladinose的大环内酯类药物在诱导erm表达方面具有活性。我们还看到了报告人被各种酮醇化物（例如泰利霉素和红霉素）诱导。这与文献中将酮酚类药物归类为非诱导剂的报道相反。使用引物延伸分析在erm系统中证实了报告者的反应。我们得出的结论是，酮醇内酯可以诱导erm表达，尽管与大环内酯类药物（如红霉素）相比，酮洛利德的诱导速度较慢且药物浓度范围更窄。我们还研究了新生erm前导肽中序列改变的影响。我们开发了两个带有截短的前导序列的报告子变体。这些构建体显示出用酮醇化物增强的诱导，而消除了大环内酯的诱导。我们得出的结论是，erm前导序列的长度或序列的微小变化会影响特定药物充当诱导剂的能力。如果在临床上做到这一点，那么既具有传统形式的可诱导性erm又具有酮内酯可诱导变异体的细胞，在用大环内酯或酮内酯药物治疗时，将对所有MLS B药物产生耐药性。总体而言，这项工作的影响是三方面的。我们开发的报告系统可用于研究诱导erm表达的各个方面，以及研究药物依赖性核糖体失速的分子机制。第二，我们已经提供了证据，例如酮醇内酯等“非诱导”药物实际上可以诱导可诱导的erm基因的表达。因此，预期使用低剂量酮缩酮长期治疗的不适当抗生素治疗会导致耐药性的发展。第三，我们证明了erm前导肽序列的改变会影响能够诱导基于erm的耐药性的抗生素谱。我们预计酮醇内酯的广泛临床应用将选择可被酮内酯类抗生素诱导的erm变异体。

著录项

  • 作者

    Bailey, Marne J.;

  • 作者单位

    University of Illinois at Chicago, Health Sciences Center.;

  • 授予单位 University of Illinois at Chicago, Health Sciences Center.;
  • 学科 Biology Molecular.; Biology Microbiology.; Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 161 p.
  • 总页数 161
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;微生物学;药理学;
  • 关键词

  • 入库时间 2022-08-17 11:39:13

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