High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis
High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis
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DOI：
10.1021/cb0500042
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Tonge, Peter J.
中科院分区：
文献类型：
--
作者：
Sullivan, Todd J.;Truglio, James J.;Tonge, Peter J.
治疗耐多药结核分枝杆菌（MTB）菌株的新型化疗药物需要与结核病的传播作斗争，结核病每年导致200多万人死亡。利用基于结构的药物设计，我们开发了一系列烷基二苯基醚，它们是MTB脂肪酸生物合成途径中烯酰还原酶InhA的非竞争性抑制剂。最有效的化合物对InhA的Ki值为1 nM，对耐药和药敏菌株的MIC99值为2-3 μ g mL(-1)（6-10 μ M）。MTB中InhA的过表达导致MIC99增加9-12倍，这与这些化合物靶向细胞内InhA的观点一致。此外，转录应答研究表明，烷基联苯醚不能上调一个假定的外排泵和芳香双加氧酶，这是由先导化合物三氯生触发的解毒机制。这些基于二苯醚的InhA抑制剂不需要被分枝杆菌KatG酶激活，从而绕过了对一线药物异烟肼（INH）的正常耐药机制，从而解释了它们对耐INH的MTB菌株的活性。
Novel chemotherapeutics for treating multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) are required to combat the spread of tuberculosis, a disease that kills more than 2 million people annually. Using structure-based drug design, we have developed a series of alkyl diphenyl ethers that are uncompetitive inhibitors of InhA, the enoyl reductase enzyme in the MTB fatty acid biosynthesis pathway. The most potent compound has a Ki' value of 1 nM for InhA and MIC99 values of 2-3 mu g mL(-1)(6-10 mu M) for both drug-sensitive and drug-resistant strains of MTB. Overexpression of InhA in MTB results in a 9-12-fold increase in MIC99, consistent with the belief that these compounds target InhA within the cell. In addition, transcriptional response studies reveal that the alkyl Biphenyl ethers fail to upregulate a putative efflux pump and aromatic dioxygenase, detoxification mechanisms that are triggered by the lead compound triclosan. These diphenyl ether-based InhA inhibitors do not require activation by the mycobacterial KatG enzyme, thereby circumventing the normal mechanism of resistance to the front line drug isoniazid (INH) and thus accounting for their activity against INH-resistant strains of MTB.