Thiazolino-Pyridone Compounds as Novel Drugs for Tuberculosis

项目总结/摘要 由结核分枝杆菌（Mtb）感染引起的结核病（TB）是主要原因 感染导致的死亡率。2020年，新诊断结核病患者1000万人， 人们死于这种疾病。随着结核病治疗工作的扩大， MTB 对一种或多种一线标准治疗（SoC）抗生素耐药的耐药菌株（DR-TB）正在增加， 部分原因是药物敏感性TB（DS-TB）的联合治疗（4种抗生素）持续时间长（6个月）， 这导致患者依从性差。耐药结核病的治疗时间甚至更长，通常为6-24个月， 同时服用3、4种或更多抗生素。虽然过去十年结核病药物的发展 “文艺复兴”，包括贝达喹啉的发现，新批准的方案仍然受到严重的一面 影响，并且可能成本过高。因此，具有新MoA的新药物类别可以与 迫切需要正在研制中的现有或新的结核病药物。贝达喹啉的成功， 结核分枝杆菌的能量代谢，并已显示出减少耐药结核病治疗时间的前景， 针对结核分枝杆菌呼吸作用的药物发现激增在本申请中，Fimbrion建议开发一种 噻唑啉-吡啶酮（TZP）小分子系列作为一种新型药物，具有抗结核分枝杆菌的生长抑制活性， 治疗肺结核虽然这一系列化合物的靶点目前尚不清楚，但TZPs似乎是通过破坏来发挥作用的。 结核分枝杆菌呼吸有趣的是，目前的TZP不仅具有直接的抗分枝杆菌活性，而且它们还可以 增强异烟肼（INH）的活性，INH是一种重要的一线结核病抗生素， 体外抗INH结核杆菌。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的生长抑制效力 在体外，和良好的药物样性质。因此，我们第一阶段的主要目标是改善生长抑制 同时保持和/或改善先导化合物的药物样性质， 在Mtb感染的动物模型中优化化合物。具体来说，我们将1）使用药物化学药物 设计策略以改善体外效价、代谢稳定性和溶解性，并将建立体内 优化的TZP在小鼠中的药代动力学（PK）特征（包括口服生物利用度）;和2）研究优化的TZP在小鼠中的药代动力学（PK）特征（包括口服生物利用度）。 体外和体内功效的优先铅TZP和产生自发突变体耐这些 化合物，以更好地了解细菌的目标和MoA。正如我们发现的， 我们的TZP的效力与其增强INH的能力有关，我们将继续抽查这种次要的 在我们的TZP的优化过程中，在这项计划完成后，我们预计会找出一个 先进的铅TZP化合物，在急性TB的小鼠模型中证明了疗效，这可以进一步 在未来的II期SBIR项目中开发，作为治疗DS-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.