Heterocyclic Inhibitors of QcrB as Novel Drugs for Tuberculosis

结核病（TB）是由结核分枝杆菌（Mtb）感染引起的，是结核病的主要病原体。 是世界上唯一一种传染病的致死原因。随着结核病治疗工作的扩大， 耐多药结核病（MDR-TB），对一线标准治疗（SOC）抗生素具有耐药性 利福平和异烟肼的比例正在上升。尽管迫切需要针对耐药结核病的新疗法， 在过去的40年里，一种新的抗生素已经进入临床用于治疗耐多药结核病， 批准的该类药物贝达喹啉具有显著的副作用，包括死亡。因此，新 以与现有药物敏感性结核病和耐多药结核病SOC协同作用的方式靶向结核分枝杆菌的药物类别 迫切需要治疗。为此，Fimbrion已将一系列 具有体外抗结核分枝杆菌抑制和杀菌活性的杂环化合物。这项技术起源于 在华盛顿大学和圣刘易斯大学，这些系列中最有影响力的成员 在低纳摩尔范围内的抑制剂浓度（IC 50）下的活性。该化合物系列的目标是 QcrB蛋白是结核分枝杆菌呼吸电子传递链的一个组成部分，这表明这些化合物 通过干扰呼吸抑制结核分枝杆菌生长和存活。QcrB最近被确定为一种可行的 治疗结核病的药物靶标，但我们的化合物系列与QcrB相比具有独特的结构 抑制剂Q203目前正在临床试验中，我们的化合物在体外具有杀菌活性，而 Q203的杀菌活性尚未报道。虽然这种支架的许多理化性质是 适合药物开发，我们已经产生了一些非常有效的化合物，低代谢稳定性 到目前为止，这是一个负担。因此，优化稳定性，同时保持效力，将是我们的优先事项。 化学优化工作。我们的项目建议书的主要目标是开发一系列的小说 具有改善的药代动力学（PK）性质的杂环QcrB抑制剂， 在Mtb感染的动物模型中治疗TB。为了实现这一目标，我们将扩大我们的化合物库， 关注杂环的两个子类，以发现和优化候选先导系列， 增加代谢稳定性，同时保持效力并使细胞毒性最小化。正确引导铅 系列鉴定和优化，我们将首先选择早期的先导化合物，然后再优化先导化合物 系列化合物，具有高效力和增加的体内PK稳定性。PK有利的候选电极导线 将测试对10种不同药物敏感和MDR Mtb菌株的体外活性 以及与贝达喹啉的协同作用，贝达喹啉也靶向结核分枝杆菌呼吸。然后我们会证明 测试先进的铅系列化合物是否可以在动物中具有体内功效的原理实验 急性结核分枝杆菌肺部感染动物模型。拟议的研究有可能导致开发 一种新的抗分枝杆菌药物家族，用于治疗药物敏感性和耐药性结核病。

Tuberculosis (TB) is caused by infection with the bacterium Mycobacteria tuberculosis (Mtb) and is the leading cause of mortality in the world for a single infectious agent. As efforts to treat TB expand, the prevalence of multidrug resistant TB (MDR-TB), which are resistant to the frontline standard of care (SOC) antibiotics rifampicin and isoniazid, is increasing. Despite the dire need for new treatments against drug resistant TB, only one new class of antibiotics has made it into the clinic for treatment of MDR-TB in the past 40 years and the approved drug from this class, bedaquiline, has significant side effects, including death. Therefore, new classes of drugs that target Mtb in ways that synergize with existing drug sensitive TB and MDR-TB SOC therapies are desperately needed. To this end, Fimbrion has in-licensed the intellectual property for a series of heterocyclic compounds with inhibitory and bactericidal activity against Mtb in vitro. This technology originated at Washington University and Saint Louis University, and the most potent members of these series have activity at inhibitor concentrations (IC50) in the low nanomolar range. The target of this compound series is the QcrB protein, a component of the respiratory electron transport chain in Mtb, suggesting that these compounds inhibit Mtb growth and survival through disrupting respiration. QcrB has recently been identified as a viable drug target for treating TB, but our compound series has a unique structure compared to the one QcrB inhibitor, Q203, that is currently in clinical trials and our compounds have bactericidal activity in vitro, whereas bactericidal activity has not been reported for Q203. While many physiochemical properties of this scaffold are suitable for drug development and we have generated some very potent compounds, low metabolic stability has thus far been a liability. Therefore, optimizing stability, while maintaining potency, will be a priority of our chemical optimization efforts. The main goal or our project proposal is to develop a lead series of novel heterocyclic QcrB inhibitors with improved pharmacokinetic (PK) properties that will be capable of effectively treating TB in an animal model of Mtb infection. To achieve this goal, we will expand our library of compounds, focusing on two subclasses of heterocycles in order to discover and optimize candidate lead series with increased metabolic stability, while maintaining potency and minimizing cellular toxicity. To properly direct lead series identification and optimization, we will select early lead compounds initially and then later optimized lead series compounds with high potency and increased stability for in vivo PK. Candidate leads with favorable PK profiles will be tested for in vitro activity against a collection of 10 diverse drug-sensitive and MDR Mtb strains as well as for synergy with bedaquiline, which also targets Mtb respiration. We will then perform proof of principle experiments to test whether an advanced lead series compound can have in vivo efficacy in an animal model of acute Mtb lung infection. The proposed studies have the potential to result in the development of a new family of anti-mycobacterials for use against both drug-sensitive and drug-resistant TB.