The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism -: Novel insights into drug mechanisms of action
The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism -: Novel insights into drug mechanisms of action
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DOI：
10.1074/jbc.m406796200
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发表时间：
2004-09-17
影响因子：
4.8
通讯作者：
Barry, CE
中科院分区：
文献类型：
--
作者：
Boshoff, HIM;Myers, TG;Barry, CE
监测结核分枝杆菌对药物和生长抑制条件的差异转录反应，生成包含 430 个微阵列图谱的数据集。这些概况的无偏分组独立地准确地对已知作用机制的药物进行聚类，并成功地预测了几种未知药物的作用机制。这些预测对于先前未分类机制的两种药物——吡啶吖啶酮和吩噻嗪——进行了生化验证。对该数据集的分析进一步揭示了 150 个协调调节基因的潜在簇，使人们首次了解该生物体的全部代谢潜力。这些基因簇的特征子集足以根据作用机制对所有已知药物进行分类。粗制和纯化的天然产物的转录分析可以提供有关纯化前的机制和解毒的关键信息，可用于指导药物发现过程。因此，由海洋天然产物产生的转录谱概括了纯活性成分的机制预测。潜在的基因簇进一步提供了细菌对药物引起的应激的代谢反应的基本见解，并为选择关键代谢靶点提供了合理的基础，以筛选对这种重要的人类病原体具有改进活性的新药物。
The differential transcriptional response of Mycobacterium tuberculosis to drugs and growth-inhibitory conditions was monitored to generate a data set of 430 microarray profiles. Unbiased grouping of these profiles independently clustered agents of known mechanism of action accurately and was successful at predicting the mechanism of action of several unknown agents. These predictions were validated biochemically for two agents of previously uncategorized mechanism, pyridoacridones and phenothiazines. Analysis of this data set further revealed 150 underlying clusters of coordinately regulated genes offering the first glimpse at the full metabolic potential of this organism. A signature subset of these gene clusters was sufficient to classify all known agents as to mechanism of action. Transcriptional profiling of both crude and purified natural products can provide critical information on both mechanism and detoxification prior to purification that can be used to guide the drug discovery process. Thus, the transcriptional profile generated by a crude marine natural product recapitulated the mechanistic prediction from the pure active component. The underlying gene clusters further provide fundamental insights into the metabolic response of bacteria to drug-induced stress and provide a rational basis for the selection of critical metabolic targets for screening for new agents with improved activity against this important human pathogen.