A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine.
A Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine.
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DOI：
10.1371/journal.pone.0010069
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发表时间：
2010-04-08
期刊：
影响因子：
3.7
通讯作者：
Kaushal D
中科院分区：
文献类型：
--
作者：
Dutta NK;Mehra S;Kaushal D
迫切需要新的治疗方法来控制结核病（TB）。硫利达嗪（THZ）是治疗多药和广泛耐药结核病的候选药物。我们研究了THZ对结核分枝杆菌（Mtb）的影响，通过分析基因表达谱后，在1-6小时之间的最低抑制（1x MIC）或高抑制（4x MIC）浓度的治疗。THZ调节编码膜蛋白、外排泵、氧化还原酶和参与脂肪酸代谢和有氧呼吸的酶的基因的表达。Rv 3160 c-Rv 3161 c操纵子（一种多药物转运蛋白）和Rv 3614 c/3615 c/3616 c调节子在THZ诱导下高度表达。与σB（σB调节子）共表达的显著高数量的Mt B基因被THZ处理打开。最近已证明σB可保护Mt B不受挤压损伤。我们假设THZ损伤Mt B细胞包膜，开启σB调节子的表达。与这一假设相一致，我们目前的电子显微镜数据表明，THZ调制细胞包膜的完整性。此外，Mt B在σH和σE（诱导σB表达的两个交替应激反应σ因子）中的突变体表现出对THZ的更高敏感性，表明σB的存在和表达允许Mt B抵抗THZ的影响。在THZ存在下，σB水平的条件诱导增加了Mt B的存活。THZ靶向不同的途径，因此本身可以用作多靶点抑制剂，并为联合化疗的多靶点药物开发提供策略。结果表明，由σH、σE和σB组成的Mt B sigma因子网络在保护病原体免受细胞包膜损伤中起着至关重要的作用。
Novel therapeutics are urgently needed to control tuberculosis (TB). Thioridazine (THZ) is a candidate for the therapy of multidrug and extensively drug-resistant TB. We studied the impact of THZ on Mycobacterium tuberculosis (Mtb) by analyzing gene expression profiles after treatment at the minimal inhibitory (1x MIC) or highly inhibitory (4x MIC) concentrations between 1–6 hours. THZ modulated the expression of genes encoding membrane proteins, efflux pumps, oxido-reductases and enzymes involved in fatty acid metabolism and aerobic respiration. The Rv3160c-Rv3161c operon, a multi-drug transporter and the Rv3614c/3615c/3616c regulon, were highly induced in response to THZ. A significantly high number of Mtb genes co-expressed with σB (the σB regulon) was turned on by THZ treatment. σB has recently been shown to protect Mtb from envelope-damage. We hypothesized that THZ damages the Mtb cell-envelope, turning on the expression of the σB regulon. Consistent with this hypothesis, we present electron-microscopy data which shows that THZ modulates cell-envelope integrity. Moreover, the Mtb mutants in σH and σE, two alternate stress response sigma factors that induce the expression of σB, exhibited higher sensitivity to THZ, indicating that the presence and expression of σB allows Mtb to resist the impact of THZ. Conditional induction of σB levels increased the survival of Mtb in the presence of THZ. THZ targets different pathways and can thus be used as a multi-target inhibitor itself as well as provide strategies for multi-target drug development for combination chemotherapy. Our results show that the Mtb sigma factor network comprising of σH, σE and σB plays a crucial role in protecting the pathogen against cell-envelope damage.
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影响因子：
3.1
作者：
Chen, P;Ruiz, RE;Bishai, WR
通讯作者：
Bishai, WR
影响因子：
5.2
作者：
Klitgaard, Janne K.;Skov, Marianne N.;Kolmos, Hans Jorn
通讯作者：
Kolmos, Hans Jorn
影响因子：
3.2
作者：
Fontan, P. A.;Voskuil, M. I.;Smith, I.
通讯作者：
Smith, I.
影响因子：
3.2
作者：
Lee, Jong-Hee;Karakousis, Petros C.;Bishai, William R.
通讯作者：
Bishai, William R.
DOI：
10.1016/j.ijantimicag.2007.04.016
发表时间：
2007-10-01
影响因子：
10.8
作者：
Dutta, Noton Kumar;Mazumdar, Kaushiki;Park, Jae-Hak
通讯作者：
Park, Jae-Hak