Thiazolino-Pyridone Compounds as Novel Drugs for Tuberculosis

项目摘要/摘要 结核病(TB)是由结核分枝杆菌(Mtb)感染引起的，是主要原因。 在全球范围内，由于感染而导致的死亡率。2020年，新增结核病患者1000万人，新增150万人 人们死于这种疾病。随着治疗结核病的努力扩大，耐药引起的感染的流行 山地车 对一种或多种一线护理标准(SOC)抗生素产生抗药性的菌株(DR-TB)正在增加， 部分原因是药物敏感型结核病(DS-TB)的联合治疗(4种抗生素)持续时间较长(6个月)， 这会导致患者依从性差。耐药结核病的治疗时间更长，通常从6到24个月不等， 联合服用3、4种或更多的抗生素。虽然在过去的十年里，结核病药物的开发 “复兴”，包括贝达奎兰的发现，新批准的方案仍然遭受着严重的副作用 效果和成本可能会令人望而却步。因此，具有新MOAS的新类别药物可以与 正在研制中的现有或新的结核病药物是急需的。贝达奎兰的成功，它颠覆了 结核分枝杆菌的能量代谢，并在减少DR-TB的治疗时间方面显示出希望，伴随着 针对Mtb呼吸的药物发现爆炸式增长。在此应用程序中，Fimbrion建议开发一种 抑制结核杆菌生长的TZP小分子系列新药 治疗结核病。虽然这个化合物系列的目标目前尚不清楚，但TZP似乎通过破坏发挥作用 结核分枝杆菌的呼吸。有趣的是，目前的TZP不仅具有直接的抗分枝杆菌活性，而且还可以 增强异烟肼(INH)的活性，这是一种重要的结核病一线抗生素，甚至可以恢复INH的活性 体外抗异烟肼结核分枝杆菌。我们在这个项目中的主要目标是开发一流的口服生物利用度， 抗分枝杆菌TZP化合物可能成为新的一线结核病药物方案的一部分，以帮助缩短 治疗持续时间。目前，我们最有效的TZP化合物具有亚微摩尔生长抑制效力 体外实验，并具有良好的类药物特性。因此，我们第一阶段的主要目标将是改善生长抑制 在保持和/或改善先导化合物的类药物性能的同时能够测试 结核分枝杆菌感染动物模型中的优化化合物。具体地说，我们将使用药物化学药物 设计策略以提高体外效力、代谢稳定性和溶解性，并将在体内建立 优化的TZPs在小鼠体内的药代动力学(PK)谱(包括口服生物利用度)；以及2)研究 优先处理铅TZPs的体内外效应及产生抗性的自发突变体 化合物，以更好地了解细菌靶标和MOA。正如我们发现的那样，抗分枝杆菌 我们的TZPS轨道的效力与他们增强异烟肼的能力，我们将继续抽查这个二级 在优化我们的开发区的整个过程中，我们都有自己的物业。在这个项目完成后，我们预计将确定一个 先进的铅TZP化合物在小鼠急性结核病模型中表现出的有效性，这可能会进一步 在未来的第二阶段SBIR项目中开发，作为治疗DS-TB和DR-TB的联合疗法的一部分。

Project Summary/Abstract Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), is a leading cause of mortality due to infection, globally. In 2020, 10 million people were newly diagnosed with TB and 1.5 million people died from the disease. As efforts to treat TB expand, the prevalence of infections caused by drug-resistant Mtb strains (DR-TB) that are resistant to one or more frontline standard of care (SoC) antibiotics is increasing, in part due to the long duration (6 months) of combination therapy (4 antibiotics) for drug-sensitive TB (DS-TB), which leads to poor patient adherence. Treatment for DR-TB is even longer, ranging from 6-24 months typically, with 3, 4 or more antibiotics taken in combination. While the last decade has seen a TB drug development “renaissance,” including the discovery of bedaquiline, newly approved regimens still suffer from serious side effects and can be cost prohibitive. Therefore, new classes of drugs with new MoAs that can be combined with existing or new TB drugs in the pipeline are desperately needed. The success of bedaquiline, which disrupts energy metabolism in Mtb and has shown promise in reducing treatment times for DR-TB, has accompanied an explosion of drug discovery targeting respiration in Mtb. In this application, Fimbrion proposes to develop a thiazolino-pyridone (TZP) small molecule series with growth inhibitory activity against Mtb as a novel drug for treating TB. While the target of this compound series is currently unknown, TZPs appear to act through disruption of Mtb respiration. Interestingly, current TZPs not only have direct antimycobacterial activity, but they can also potentiate the activity of isoniazid (INH), an important frontline TB antibiotic, even restoring INH activity against INH-resistant Mtb in vitro. Our primary goal in this project is to develop a first-in-class, orally bioavailable, antimycobacterial TZP compound that could become part of a new frontline TB drug regimen to help shorten the duration of treatment. Currently, our most potent TZP compounds have sub-micromolar growth inhibition potency in vitro, and favorable drug-like properties. Therefore, our primary Phase I goal will be to improve growth inhibition potency while maintaining and/or improving the drug-like properties of the lead compounds to enable testing of optimized compounds in an animal model of Mtb infection. Specifically, we will 1) use medicinal chemistry drug design strategies to improve in vitro potency, metabolic stability, and solubility, and will establish in vivo pharmacokinetic (PK) profiles (including oral bioavailability) for optimized TZPs in mice; and 2) investigate the in vitro and in vivo efficacy of prioritized lead TZPs and generate spontaneous mutants resistant to these compounds to better understand the bacterial target and MoA. As we have found that the antimycobacterial potency of our TZPs tracks with their ability to potentiate INH, we will continue to spot-check this secondary property throughout the optimization of our TZPs. Upon completion of this project, we expect to identify an advanced lead TZP compound with demonstrated efficacy in a mouse model of acute TB, which could be further developed in a future Phase II SBIR project as part of a combination therapy for treating both DS- and DR-TB.