Rifampicin-resistance, rpoB polymorphism and RNA polymerase genetic engineering
Rifampicin-resistance, rpoB polymorphism and RNA polymerase genetic engineering
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DOI：
10.1016/j.jbiotec.2014.11.024
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发表时间：
2015-05-20
影响因子：
4.1
通讯作者：
Tala, Adelfia
中科院分区：
文献类型：
--
作者：
Alifano, Pietro;Palumbo, Carla;Tala, Adelfia
自 1967 年推出以来，利福平已成为治疗结核病、麻风病和许多其他常见疾病的主要疗法。其强大的抗菌活性归因于对细菌 RNA 聚合酶的特异性抑制。然而，利福平进入医疗实践后不久就出现了耐药性。对模式生物大肠杆菌的研究有助于确定利福平耐药性的分子机制，表明耐药性主要是由于编码 RNA 聚合酶 β 链的 rpoB 基因的染色体突变所致。这些研究还揭示了分子遗传学在阐明细菌 RNA 聚合酶结构与功能关系方面的惊人潜力。本文的目的是说明最近如何利用利福平耐药性来更好地理解控制细菌细胞生理学和毒力的调节机制，以及如何利用这些信息在全球范围内操纵具有工业利益的细菌的基因表达。我们特别回顾了最近关于以下方面的文献：（i）赋予利福平耐药性的 rpoB 突变对转录动力学、细菌适应性、生理学、代谢和毒力的影响； (ii) 自然界中存在“突变型”或重复的利福平抗性 RNA 聚合酶； (iii) 用于菌株改良和药物发现的RNA聚合酶基因工程方法。 (C) 2014 Elsevier B.V. 保留所有权利。
Following its introduction in 1967, rifampicin has become a mainstay of therapy in the treatment of tuberculosis, leprosy and many other widespread diseases. Its potent antibacterial activity is due to specific inhibition of bacterial RNA polymerase. However, resistance to rifampicin was reported shortly after its introduction in the medical practice. Studies in the model organism Escherichia coli helped to define the molecular mechanism of rifampicin-resistance demonstrating that resistance is mostly due to chromosomal mutations in rpoB gene encoding the RNA polymerase beta chain. These studies also revealed the amazing potential of the molecular genetics to elucidate the structure-function relationships in bacterial RNA polymerase. The scope of this paper is to illustrate how rifampicin-resistance has been recently exploited to better understand the regulatory mechanisms that control bacterial cell physiology and virulence, and how this information has been used to maneuver, on a global scale, gene expression in bacteria of industrial interest. In particular, we reviewed recent literature regarding: (i) the effects of rpoB mutations conferring rifampicin-resistance on transcription dynamics, bacterial fitness, physiology, metabolism and virulence; (ii) the occurrence in nature of "mutant-type" or duplicated rifampicin-resistant RNA polymerases; and (iii) the RNA polymerase genetic engineering method for strain improvement and drug discovery. (C) 2014 Elsevier B.V. All rights reserved.