Aerosol spectinamide-1599 therapy against tuberculosis

总结 结核病（TB）的长期治疗是出现多药耐药的主要原因。 耐多药结核病（MDR-TB），因为它经常导致不遵守。目前针对耐多药结核病的化疗可以持续 使用多种药物方案长达两年，其中一些是疼痛的可注射药物， 毒性结核病的根除和控制取决于开发更短和更有效的治疗方法 具有最小药物相关毒性的方案。本申请中研究的一种方法是开发一种 吸入性结核病治疗[以取代注射药物]，当与口服结核病药物一起使用时， 缩短治疗时间。与可注射剂不同，雾化药物递送易于给药并提供高的给药效率。 肺浓度的抗生素的局部感染部位，从而降低全身水平 暴露于药物。最近发表在《自然医学》上的一篇由“壮观酰胺联盟”撰写的文章显示， 新的壮观酰胺类似物对结核分枝杆菌（Mtb）具有优异的活性，包括 MDR和XDR Mtb菌株在体外，以及当通过皮下注射施用时在体内。在 在同一项研究中，先导化合物壮观酰胺-1599对肺结核表现出很强的疗效， 通过肺内气溶胶（IPA）递送，将其作为液体制剂直接施用至小鼠的肺。 通过扩展我们在本申请中的初步数据，目的1将确定药代动力学（PK） 和IPA后壮观酰胺-1599的组织分布。目标2将确定最佳剂量、持续时间和 用IPA和Aim 3递送的壮观酰胺-1599处理的频率将优化干粉 本发明提供了用于吸入性TB治疗的壮观酰胺-1599制剂。这些研究将在 作为结核病、吸入性结核病动物模型和临床前研究领域专家的联合体， 肺结核化疗和气雾剂制剂的药代动力学和药效学以及 干粉位于科罗拉多州立大学，田纳西大学，三角研究所和圣。 裘德儿童研究医院这个研究小组共同努力， 这种药物的研究水平，通过壮观的酰胺吸入治疗-1599可以被认为是一种新的 结核病的药物/治疗候选药物。因此，这些研究将提供一种制剂和吸入治疗方案 具有明确的空气动力学和PK特性以及良好的体内表征的壮观酰胺-1599 在多药联合研究和大型吸入性动物TB模型中进行未来测试的有效性， 最终在结核病患者中。

Summary The lengthy treatment for tuberculosis (TB) is the primary cause of the emergence of multidrug resistant tuberculosis (MDR-TB), as it frequently results in non-compliance. Current chemotherapy for MDR-TB can last up to two years with multidrug regimens some of which are painful injectable drugs with serious associated toxicity. Eradication and control of TB depends on the development of shorter and more effective treatment regimens with minimal drug associated toxicity. One approach under study in this application is to develop an inhalational TB therapy [to replace injectable drugs] that when administered with oral TB drugs eases and shortens treatment. Aerosolized drug delivery unlike injectable agents is easy to administer and provides high pulmonary concentrations of antibiotics to the local site of infection thereby reducing the systemic level of exposure to the drug. A recently published article in Nature Medicine by the “spectinamide consortium” showed that novel spectinamide analogs have excellent activity against Mycobacterium tuberculosis (Mtb) including MDR and XDR Mtb strains in vitro, as well as in vivo when administered by subcutaneous injection. In the same study, the lead compound spectinamide-1599 demonstrated strong efficacy against pulmonary TB when administered as a liquid formulation directly to the lungs of mice via intrapulmonary aerosol (IPA) delivery. By expanding on our preliminary data in this application Aim 1 will determine the pharmacokinetics (PK) and tissue distribution of spectinamide-1599 after IPA. Aim 2 will determine optimal dose, duration and frequency for treatment with spectinamide-1599 delivered by IPA and Aim3 will optimize a dry powder formulation of spectinamide-1599 to be used as inhalational TB therapy. These studies will be developed as a consortium between experts in the field of TB, inhalational animal models of TB and preclinical studies, pharmacokinetics and pharmacodynamics of TB chemotherapy and aerosol formulations and formulation of dry powders located at Colorado State University, University of Tennessee, Research Triangle Institute and St. Jude Children's Research Hospital. Working all together this consortium of researchers aims to advance research for this drug to the level that inhalational therapy via spectinamide-1599 can be considered a new drug/therapy candidate for TB. Thus, these studies will provide a formulation and inhalational therapy regimen of the spectinamide-1599 with well defined aerodynamic and PK properties and of well characterized in vivo efficacy for future testing in multidrug combination studies and in larger inhalational animal TB models and ultimately in TB patients.