JHU- Optimal regimen development on a Ribosome inhibitor backbone.

项目摘要 结核分枝杆菌（Mycobacterium tuberculosis，Mtb）是结核病（TB）的病原体，在世界范围内造成了更多的死亡 比任何单一的传染源都要多基于利福霉素的标准治疗（SOC）方案有效，但 需要6个月的治疗，这使得它很难在全球范围内实施。尽管高剂量利福霉素方案 目前正在试验可能将治疗缩短至4个月的方案，但这些方案和SOC都不会 利福霉素耐药或耐多药（MDR-）结核病患者受益，其中约60万例新发 案件发生在2016年。目前的耐多药结核病治疗方案是有毒的，需要9-24个月的管理 只能治愈50%的病人包含3种或3种以上新药的新治疗方案的可用性 没有预先存在的耐药性可能是转型，特别是如果治疗缩短效果 利福霉素可以被替代。该联盟的总体目标是（i）发现和开发新型结核病 靶向细菌蛋白质代谢抑制的各个方面的候选药物（协同合成和 降解蛋白质），以及（ii）将这些候选物联合收割机组合成能够缩短时间的新型3-或4-药物方案 药物敏感性结核病或RR-TB的治疗。项目1-3将侧重于确定和促进 临床前候选药物，每种药物都靶向蛋白质稳定机制的一个组成部分（[1] ClpC 1，[2] ClpP 1 P2 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种互补的鼠TB模型（“标准”BALB/c小鼠、具有更多人- 如干酪样[坏死]肺病变，免疫功能低下的裸鼠），项目4，这是在本 应用，将（1）表征控制杀菌活性的杀菌-应答关系， 项目1-3中出现的铅化合物的耐药性抑制，以及TBI-223的毒性 再加上TBI-223，结核病重点恶唑烷酮，这已经是一个临床前的候选人赞助的结核病 联盟，（2）评估干酪化肺病变对这些疗效-反应关系的影响，和（3） 开发最有效的药物组合，其中包含最佳剂量的临床前候选药物 并在预测性小鼠中评价其相对于SOC的治疗缩短潜力 模型总体目标是开发一种或多种药效学优化的、普遍活性的、 靶向Mtb蛋白质稳态的治疗缩短方案。因为这项工作将发生在一个 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 来自项目1-4的新产品也可以与其他有前途的临床前先导产品/候选产品组合， 靶向蛋白质代谢抑制以外机制的临床候选药物，从而扩大潜在机会 来发现转化方案。

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.