Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization
Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization
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DOI：
10.1073/pnas.96.22.12833
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发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Schoolnik, GK
中科院分区：
文献类型：
--
作者：
Wilson, W;DeRisi, J;Schoolnik, GK
结核病是一种慢性传染病，通过携带致病细菌结核分枝杆菌的咳嗽飞沫传播。虽然目前可用的药物可以杀死大多数结核分枝杆菌分离株，但已经出现了对每种结核分枝杆菌都具有耐药性的菌株，而且多重耐药菌株越来越普遍。日益严重的耐药性问题加上全球每年700万新病例的发病率，突出表明迫切需要新的抗结核疗法。最近发表的结核分枝杆菌基因组完整序列，首次使对这种有机体的生物学和药物发现过程的全面基因组方法成为可能。我们使用含有该序列预测的97%的orf的DNA微阵列来监测抗结核药物异烟肼对结核分枝杆菌基因表达的影响。在这里，我们表明异烟肼诱导了几个基因，这些基因编码的蛋白质在生理上与药物的作用方式相关。包括一个由5个基因组成的操纵子簇，编码II型脂肪酸合成酶和编码海藻糖二真菌基转移酶的fbpC。其他不明显直接影响生物合成途径的基因也被诱导。这些基因。efpA、fadE23、fadE24和ahpC可能介导与药物毒性后果相关的过程。从这种方法中获得的见解可能会定义新的药物靶点，并提出识别抑制这些靶点的化合物的新方法。
Tuberculosis is a chronic infectious disease that is transmitted by cough-propelled droplets that carry the etiologic bacterium, Mycobacterium tuberculosis. Although currently available drugs kill most isolates of M. tuberculosis, strains resistant to each of these have emerged, and multiply resistant strains are increasingly widespread. The growing problem of drug resistance combined with a global incidence of seven million new cases per year underscore the urgent need for new antituberculosis therapies. The recent publication of the complete sequence of the M. tuberculosis genome has made possible, for the first time, a comprehensive genomic approach to the biology of this organism and to the drug discovery process. We used a DNA microarray containing 97% of the ORFs predicted from this sequence to monitor changes in M, tuberculosis gene expression in response to the antituberculous drug isonianid. Here we show that isoniazid induced several genes that encode proteins physiologically relevant to the drug's mode of action. including an operonic cluster of five genes encoding type II fatty acid synthase enzymes and fbpC, which encodes trehalose dimycolyl transferase. Other genes, not apparently within directly affected biosynthetic pathways, also were induced. These genes. efpA, fadE23, fadE24, and ahpC, likely mediate processes that are linked to the toxic consequences of the drug. Insights gained from this approach may define new drug targets and suggest new methods for identifying compounds that inhibit those targets.