InbR, a TetR family regulator, binds with isoniazid and influences multidrug resistance in Mycobacterium bovis BCG

在Scientific Reports上面的一篇论文昨天(2015-9-10)上线了。我是第二作者,负责了ChIP-seq实验等少部分实验,全部的生物信息学分析,论文撰写、修订和投稿等事宜。该研究最初投稿的是核酸研究杂志,被拒稿后由我接手,转投Scientific Reports,前后耗费了2个多月终于接受。除了正文中,附件也有不少数据,特别是一个大Table。

www.nature.com/articles/srep13969
论文摘要如下:

Isoniazid (INH), an anti-tuberculosis (TB) drug, has been widely used for nearly 60 years. However, the pathway through which Mycobacterium tuberculosis responds INH remain largely unclear. In this study, we characterized a novel transcriptional factor, InbR, which is encoded by Rv0275c and belongs to the TetR family, that is directly responsive to INH. Disrupting inbR made mycobacteria more sensitive to INH, whereas overexpressing inbR decreased bacterial susceptibility to the drug. InbR could bind specifically to the upstream region of its own operon at two inverted repeats and act as an auto-repressor. Furthermore, InbR directly bind with INH, and the binding reduced InbR’s DNA-binding ability. Interestingly, susceptibilities were also changed by InbR for other anti-TB drugs, such as rifampin, implying that InbR may play a role in multi-drug resistance. Additionally, microarray analyses revealed a portion genes of the inbR regulon have similar expression patterns in inbR-overexpressing strain and INH-treated wild type strain, suggesting that these genes, for example iniBAC, may be responsible to the drug resistance of inbR-overexpressing strain. The regulation of these genes by InbR were further assessed by ChIP-seq assay. InbR may regulate multiple drug resistance of mycobacteria through the regulation of these genes.

在这篇论文中,我们发现了一个能够与INH结合的转录因子。该转录因子能够和INH结合,受INH的诱导,并能调控分枝杆菌的多重耐药性。这是一个很有意义的发现。

我们发现,转录因子对抗药性的影响与代谢酶类存在不同。如结核分枝杆菌中KatG, InhA, RpoB等酶突变可能会引起抗药性显著的、不可控的和不可逆转的变化,而转录因子则存在“商量”的余地。这可能是因为转录因子是以网络化结构发挥作用的。单个转录因子的突变的影响甚至可以通过调节适应下来。

转录因子与抗药性的关系,以及通过转录因子来设计新药治疗结核病,虽然尚在路上,但应当是一个很有意思的课题。

全文下载点这里

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