Identification of gene targets against dormant phase Mycobacterium tuberculosis infections.
Identification of gene targets against dormant phase Mycobacterium tuberculosis infections.
复制标题
鉴定针对休眠期分枝杆菌感染的基因靶标。
DOI：
10.1186/1471-2334-7-84
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发表时间：
2007-07-26
影响因子：
3.7
通讯作者：
Brown JR
中科院分区：
文献类型：
--
作者：
Murphy DJ;Brown JR
结核分枝杆菌（Mycobacterium tuberculosis）是结核病（TB）的病原体，感染全世界约20亿人，并且是由于传染病导致死亡的主要原因。目前的结核病治疗包括在六个月内服用四种抗生素的方案。患者依从性、药物成本和耐药M发生率的增加。结核菌株的增加增加了开发新的结核疗法的紧迫性。结核病的根除受到细菌在休眠状态下存活长达数十年的能力的影响，主要是在肺中的缺氧肉芽肿中，并引起复发性感染。M.结核病全基因组DNA微阵列导致了在模拟休眠条件下的几个基因表达研究的发表。然而，没有一个单一的模型最好地复制人类致病性的条件。为了确定新的结核病药物靶点，我们对来自基因表达DNA微阵列实验的多个已发表数据集进行了荟萃分析，这些实验模拟了导致并包括休眠状态的感染，沿着来自检查基因必要性的全基因组插入诱变的数据。基于标准化后对这些数据集的分析，确定了几个全基因组趋势，并用于指导治疗开发的靶点选择。这些趋势包括devR控制的基因显著上调，蛋白质和ATP合成的下调，以及二碳代谢对肉芽肿缺氧和营养限制环境的适应。有希望的药物发现的目标是几个调节元件（devR/devS，relA，mprAB），参与氧化还原平衡和呼吸，硫运输和固定，泛酸，异戊二烯和NAD生物合成的酶。每一个目标的优点和责任进行了讨论的背景下，酶学，细菌途径，目标tractability，和药物开发。基于我们的生物信息学分析和深入的生物学原理的额外讨论，已经提出了几种新的抗TB靶点作为改善这种疾病的现有治疗方法的潜在机会。
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects approximately 2 billion people worldwide and is the leading cause of mortality due to infectious disease. Current TB therapy involves a regimen of four antibiotics taken over a six month period. Patient compliance, cost of drugs and increasing incidence of drug resistant M. tuberculosis strains have added urgency to the development of novel TB therapies. Eradication of TB is affected by the ability of the bacterium to survive up to decades in a dormant state primarily in hypoxic granulomas in the lung and to cause recurrent infections. The availability of M. tuberculosis genome-wide DNA microarrays has lead to the publication of several gene expression studies under simulated dormancy conditions. However, no single model best replicates the conditions of human pathogenicity. In order to identify novel TB drug targets, we performed a meta-analysis of multiple published datasets from gene expression DNA microarray experiments that modeled infection leading to and including the dormant state, along with data from genome-wide insertional mutagenesis that examined gene essentiality. Based on the analysis of these data sets following normalization, several genome wide trends were identified and used to guide the selection of targets for therapeutic development. The trends included the significant up-regulation of genes controlled by devR, down-regulation of protein and ATP synthesis, and the adaptation of two-carbon metabolism to the hypoxic and nutrient limited environment of the granuloma. Promising targets for drug discovery were several regulatory elements (devR/devS, relA, mprAB), enzymes involved in redox balance and respiration, sulfur transport and fixation, pantothenate, isoprene, and NAD biosynthesis. The advantages and liabilities of each target are discussed in the context of enzymology, bacterial pathways, target tractability, and drug development. Based on our bioinformatics analysis and additional discussion of in-depth biological rationale, several novel anti-TB targets have been proposed as potential opportunities to improve present therapeutic treatments for this disease.
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影响因子：
3.2
作者：
Daniel, J;Deb, C;Kolattukudy, PE
通讯作者：
Kolattukudy, PE
DOI：
10.1073/pnas.1631248100
发表时间：
2003-08-19
影响因子：
11.1
作者：
Dahl, JL;Kraus, CN;Barry, CE
通讯作者：
Barry, CE
影响因子：
56.9
作者：
Andries, K;Verhasselt, P;Jarlier, V
通讯作者：
Jarlier, V
影响因子：
3.1
作者：
Dawes, SS;Warner, DF;Mizrahi, V
通讯作者：
Mizrahi, V
影响因子：
--
作者：
Erickson, MG;Ulijasz, AT;Weisblum, B
通讯作者：
Weisblum, B