JHU- Optimal regimen development on a Ribosome inhibitor backbone.

项目总结 结核分枝杆菌(Mtb)是结核病(TB)的病原体，在全球范围内造成更多的死亡 比任何单一的感染源都要强。以利福霉素为基础的标准护理(SOC)方案是有效的，但 需要6个月的治疗，使其难以在全球范围内实施。虽然大剂量利福霉素方案 这可能会将治疗缩短到4个月，目前正在试验中，这些方案和SOC都不会 使耐利福霉素或多药耐药(MDR)结核病患者受益，其中约60万名新患者 病例发生在2016年。目前耐多药结核病的治疗方案是有毒的，需要9-24个月的服药 而且只治愈了大约50%的患者。包含3个或更多新药类别的新方案的可用性 如果没有预先存在的耐药性，可能是变革性的，特别是如果 利福霉素是可以替代的。该联盟的总体目标是：(I)发现和开发新的结核病 靶向细菌蛋白平衡的各个方面的候选药物(协调合成和 降解蛋白质)，以及(Ii)将这些候选组合成能够缩短的新的3-或4-药物方案 药物敏感或RR-TB的治疗。项目1-3将侧重于确定和推进 临床前候选，每个都针对蛋白质平衡机制的一个组件([1]ClpC1，[2]ClpP1P2 蛋白酶，[3]RNA聚合酶)。使用体外药效学系统(中空纤维)的组合 模型)和3个互补的小鼠结核病模型(“标准”BALB/c小鼠，C3H3B/FEJ小鼠与更多的人- 如干酪性[坏死性]肺损伤、免疫功能低下的裸鼠)，项目4 应用，将(1)表征支配杀菌活性的暴露-反应关系， 项目1-3中出现的铅化合物的抗药性抑制和毒性 加上TB-223，专注于结核病的恶唑烷酮，已经是TB赞助的临床前候选药物 联盟，(2)评估干酪性肺部病变对这些暴露-反应关系的影响，以及(3) 开发最有效的药物组合，包含正在出现的临床前候选药物的最佳剂量 来自项目1-4，并评估它们相对于预测小鼠的SOC的治疗缩短潜力 模特们。首要目标是开发一种或多种药物动力学优化、普遍有效、 针对结核分枝杆菌蛋白抑制的缩短治疗方案。因为这项工作将在 由结核病联盟临床前候选人赞助的强大、高度协作的结核病药物开发计划 从项目1-4中脱颖而出的项目也可以与其他有希望的临床前线索/候选人相结合 针对蛋白抑制以外的机制的临床候选对象，从而放大了潜在的机会 发现变革性的养生法。

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), causes more deaths worldwide than any single infectious agent. The rifamycin-based standard-of-care (SOC) regimen is efficacious but requires 6 months of treatment, making it difficult to implement globally. Although high-dose rifamycin regimens that may shorten treatment to 4 months are currently being trialed, neither these regimens nor the SOC will benefit patients with rifamycin-resistant or multidrug-resistant (MDR-) TB, of which approximately 600,000 new cases occurred in 2016. Current MDR-TB treatment regimens are toxic, require 9-24 months of administration and cure only about 50% of patients. The availability of new regimens containing 3 or more novel drug classes without pre-existing resistance could be transformational, especially if the treatment-shortening effects of rifamycins could be replaced. The overall objectives of the consortium are (i) to discover and develop novel TB drug candidates targeting various aspects of bacterial proteostasis (the capacity to coordinately synthesize and degrade proteins), and (ii) to combine these candidates into novel 3- or 4-drug regimens capable of shortening the treatment of drug-susceptible or RR-TB. Projects 1-3 will focus on the identification and advancement of preclinical candidates, each targeting a component of the proteostasis machinery ([1] ClpC1, [2] ClpP1P2 protease, [3] RNA polymerase). Using a combination of an in vitro pharmacodynamics system (hollow fiber model) and 3 complementary murine TB models (“standard” BALB/c mice, C3H3B/FeJ mice with more human- like caseous [necrotic] lung lesions, immunocompromised nude mice), Project 4, which is described in this application, will (1) characterize the exposure-response relationships that govern bactericidal activity, resistance suppression and, in the case of TBI-223, toxicity of lead compounds emerging from Projects 1-3 plus TBI-223, the TB-focused oxazolidinone, which is already a pre-clinical candidate sponsored by TB Alliance, (2) evaluate the impact of caseating lung lesions on these exposure-response relationships, and (3) develop the most effective drug combinations containing the optimal doses of pre-clinical candidates emerging from Projects 1-4 and evaluate their treatment-shortening potential relative to the SOC in predictive murine models. The overarching goal is to develop one or more pharmacodynamically-optimized, universally active, treatment-shortening regimens targeting Mtb proteostasis. Because this effort will occur in the context of a robust, highly collaborative TB drug development program sponsored by TB Alliance pre-clinical candidates emerging from Projects 1-4 may also be combined with other promising pre-clinical leads/candidates and clinical candidates that target mechanisms other than proteostasis, thus amplifying the potential opportunities for discovery of transformational regimens.