Understanding the action of INH on a highly INH-resistant Mycobacterium tuberculosis strain using GeneChips
Understanding the action of INH on a highly INH-resistant Mycobacterium tuberculosis strain using GeneChips
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DOI：
10.1016/j.tube.2006.04.001
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发表时间：
2007-01-01
期刊：
影响因子：
3.2
通讯作者：
Shinnick, Thomas M.
中科院分区：
文献类型：
--
作者：
Fu, Li M.;Shinnick, Thomas M.
结核分枝杆菌全基因组序列的可获得性与微阵列技术相结合，使得高通量方法能够对这种生物的药物基因组学进行研究。异烟肼(INH)是治疗结核病的一线药物，微阵列方法使人们对异烟肼对药物敏感菌株的作用有了新的认识。它还表明，当INH应用于Catatase阴性的INH抗性菌株时，不会诱导任何显著的基因表达变化，这是预期的，因为需要过氧化氢酶活性才能将前药INH转化为其活性形式。但尚未确定部分耐药菌株对异烟肼的反应。在这项研究中，我们探索了异烟肼对高度异烟肼耐药株的作用机制，比较了耐药株和敏感株之间的药物诱导基因表达谱，并确定耐药株是否以及如何对低浓度和高浓度的异烟肼做出反应。使用Affymetrix寡核苷酸GeneChips获得了抗药性菌株对异烟肼处理的响应的整体基因表达谱。结果表明，耐药品系在低浓度异烟肼作用下没有表现出抑制II型脂肪酸合成酶(Fas-II)的特征基因表达特征，但在高水平异烟肼作用下表现出这种特殊的反应模式，尽管与敏感品系相比，反应谱有所缩小。我们发现异烟肼在耐药株和敏感株中都作用于Fas-II途径，几乎没有证据表明异烟肼可能通过其他机制杀死耐药细菌。这表明，在有效和安全的水平上用异烟肼治疗异烟肼耐药细菌可能有潜在的好处。(C)2006爱思唯尔有限公司。保留所有权利。
The availability of the complete sequence of Mycobacterium tuberculosis genome coupled with microarray technology has enabled a high-throughput approach to the pharmacogenomics of this organism. Isoniazid (INH) is a first-line drug for the treatment of tuberculosis and the microarray approach has generated new insight into the action of INH on a drug-susceptible strain. It has also shown that INH does not induce any significant change in gene expression when applied to a catatase-negative INH-resistant strain, which is expected because catalase activity is required to convert the prodrug INH to its active form. But it has yet to be determined how a partially resistant strain responds to INH. In this study, we explore the mechanism of INH against a highly INH-resistant strain, compare drug-induced gene-expression profiles between resistant and susceptible strains, and determine whether or not and how the resistant strain responds to INH at low and high concentrations. The global gene-expression profiles of the resistant strain in response to INH treatments were obtained using the Affymetrix oligonucleotide GeneChips. The results showed that the resistant strain did not exhibit the characteristic gene-expression signature of type II fatty acid synthase (FAS-II) inhibition when exposed to low-level INH, but it responded with that specific pattern under high-level INH, although the response profile was somewhat shrunken relative to that for a susceptible strain. We found that INH acted on the FAS-II pathway in both resistant and susceptible strains, and little evidence suggested that INH might kill resistant bacteria via other mechanisms. This suggests that there may be potential benefit of treating INH-resistant bacteria with INH at a level that is effective and safe. (c) 2006 Elsevier Ltd. All rights reserved.