Inhibitors of Mycobacterium tuberculosis FAS-II dehydratases

项目摘要 由结核分枝杆菌（Mycobacterium tuberculosis，Mtb）引起的结核病（tuberculosis，TB）仍然是一个主要的公共卫生问题 艾滋病毒感染者中最常见的疾病占四分之一 与艾滋病毒/艾滋病有关的死亡。耐多药结核病菌株的持续增加使得结核病的发展 新的有效的抗结核病药物的高度优先事项。在此背景下，重新审视分子作用机制 已建立的抗结核药物，其靶向与一线抗结核药物相同的经过充分验证的生物合成途径， 结核病药物，但在一个独特的催化步骤，从而绕过广泛的耐药机制，可能有一个 对耐药结核病的治疗产生重大影响。先前用于临床的两种这样的前药 结核病的治疗，Isoxyl（ISO）和Thiacetazone（TAC），一直是我们研究的对象。我们 鉴定了必需的FAS-II脂肪酶，HadAB，作为ISO和TAC的靶向酶， 分枝菌酸的生物合成，并阐明了一些最常见的耐药机制与 该酶在结核分枝杆菌中的抑制。 科罗拉多州立大学和开普敦大学最近的合作研究 发现和发展中心（H3 D）（南非），导致了新一代的发现， HadAB抑制剂，结构上与ISO和TAC无关，对整个Mtb杆菌显示出有效的活性。 初步的作用模式研究表明，这些化合物：（i）与ISO和TAC不同，不需要 由单加氧酶EthA激活;（ii）与HadAB的相互作用不同于以前的药物;和（iii） 它们中的一个子集具有抑制FAS-II的第二种脂肪酶HadBC的能力，这导致了一些 的耐药机制与HadAB抑制结核分枝杆菌。因此，这种新的化合物系列 有可能绕过与化学品相关的一些最常见的耐药机制 Mtb HadAB的抑制。 该提议旨在开发基于H3 D化合物的新的有效治疗剂，用其治疗Mtb 感染.这一目标将通过优化现有的命中通过化学类比（目标1），生物 分析（目标2）和新兴电极导线的体内有效性测试（目标3）。

Project Summary Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem worldwide and the most common presenting illness among people living with HIV accounting for one in four HIV/AIDS-associated deaths. The continuing rise of multidrug-resistant strains of Mtb makes the development of new effective anti-TB drugs a high priority. In this context, re-examining the molecular mechanism of action of established antitubercular drugs that target the same well-validated biosynthetic pathway as front-line anti- TB agents but at a distinct catalytic step, thereby bypassing widespread resistance mechanisms, could have a major impact on the treatment of drug-resistant TB. Two such prodrugs previously used in the clinical treatment of TB, Isoxyl (ISO) and Thiacetazone (TAC), have been the object of our investigations. We identified the essential FAS-II dehydratase, HadAB, as the enzyme targeted by both ISO and TAC to inhibit mycolic acid biosynthesis and elucidated some of the most common mechanisms of resistance associated with the inhibition of this enzyme in Mtb. Recent collaborative studies between Colorado State University and the University of Cape Town Drug Discovery and Development Centre (H3D) (South Africa), have led to the discovery of a new generation of HadAB inhibitors, structurally unrelated to ISO and TAC, that displays potent activity against whole Mtb bacilli. Preliminary mode of action studies indicate that these compounds: (i) unlike ISO and TAC, do not require activation by the monooxygenase EthA; (ii) interact with HadAB differently from the former drugs; and (iii) that a subset of them have the ability to inhibit the second dehydratase of FAS-II, HadBC, which accounts for some of the resistance mechanisms associated with HadAB inhibition in Mtb. As a result, this new compound series has the potential to bypass some of the most common resistance mechanisms associated with the chemical inhibition of Mtb HadAB. This proposal aims to develop novel effective therapeutics based on H3D’s compounds with which to treat Mtb infections. This goal will be achieved by optimizing existing hits through chemical analoging (Aim 1), biological profiling (Aim 2) and in vivo efficacy testing of emerging leads (Aim 3).