Targeting tuberculosis and malaria through inhibition of enoyl reductase
Targeting tuberculosis and malaria through inhibition of enoyl reductase
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DOI：
10.1074/jbc.m211968200
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发表时间：
2003-06-06
影响因子：
4.8
通讯作者：
Fidock, DA
中科院分区：
文献类型：
--
作者：
Kuo, MR;Morbidoni, HR;Fidock, DA
据估计，结核病和疟疾每年共造成500万人死亡。最具致病性的病原体结核分枝杆菌和恶性疟原虫的多重耐药蔓延，强调了鉴定具有新型抑制特性的活性化合物的必要性。虽然基因无关，但这两种生物都使用II型脂肪酸合成酶系统。烯丙酰基载体蛋白还原酶（ENR）是一种关键的II型酶，已被反复证实是一种有效的抗菌靶点。利用组合文库的高通量抑制剂筛选，我们鉴定了两类具有抗结核分枝杆菌和恶性疟原虫酶活性的新化合物（分别称为InhA和PfENR）。测定了InhA与NAD（+）和其中一种抑制剂配合的晶体结构，以阐明其结合方式。对InhA与广谱抗菌三氯生的结构分析揭示了一种独特的化学计量，其中酶要么含有单个三氯生分子，在其他细菌ENR的典型配置中：三氯生结构，要么含有两个与活性位点结合的三氯生分子。值得注意的是，这些化合物不需要激活，并且对结核分枝杆菌和恶性疟原虫的野生型和耐药菌株有效。此外，它们提供了更广泛的化学多样性，并阐明了抑制剂与InhA结合的关键元素，为后续的化学优化提供了基础。
Tuberculosis and malaria together result in an estimated 5 million deaths annually. The spread of multidrug resistance in the most pathogenic causative agents, Mycobacterium tuberculosis and Plasmodium falciparum, underscores the need to identify active compounds with novel inhibitory properties. Although genetically unrelated, both organisms use a type II fatty-acid synthase system. Enoyl acyl carrier protein reductase (ENR), a key type II enzyme, has been repeatedly validated as an effective antimicrobial target. Using high throughput inhibitor screens with a combinatorial library, we have identified two novel classes of compounds with activity against the M. tuberculosis and P. falciparum enzyme (referred to as InhA and PfENR, respectively). The crystal structure of InhA complexed with NAD(+) and one of the inhibitors was determined to elucidate the mode of binding. Structural analysis of InhA with the broad spectrum antimicrobial triclosan revealed a unique stoichiometry where the enzyme contained either a single triclosan molecule, in a configuration typical of other bacterial ENR: triclosan structures, or harbored two triclosan molecules bound to the active site. Significantly, these compounds do not require activation and are effective against wild-type and drug-resistant strains of M. tuberculosis and P. falciparum. Moreover, they provide broader chemical diversity and elucidate key elements of inhibitor binding to InhA for subsequent chemical optimization.