JHU- Optimal regimen development on a Ribosome inhibitor backbone.

JHU-核糖体抑制剂骨干上的最佳方案开发。

基本信息

批准号：
10388415
负责人：
ERIC L NUERMBERGER
金额：
$ 85.09万
依托单位：
GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388415
关键词：
ATP phosphohydrolase Anti-Bacterial Agents Biological Assay C3HeB/FeJ Mouse Cell Line Cessation of life Collaborations DNA-Directed RNA Polymerase Data Development Dose Drug Combinations Drug Exposure Drug resistance Drug resistant Mycobacteria Tuberculosis Etiology Fiber Goals Growth Human Hypoxia Immunocompromised Host In Vitro Inbred BALB C Mice Infection Infectious Agent K562 Cells Lead Lesion Linezolid Methods Mitochondria Mitochondrial Proteins Modeling Multidrug-Resistant Tuberculosis Mus Mycobacterium tuberculosis Necrosis Nude Mice Oxazolidinones Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacodynamics Production Program Development Protein Synthesis Inhibition Proteins Regimen Resistance Ribosomes Rifamycins Sterilization System Time Toxic effect Treatment Protocols Tuberculosis Vertebral column active method bactericide base clinical candidate comparative drug candidate drug distribution drug-sensitive experimental study in vitro Assay in vitro Model in vitro activity inhibitor lead candidate leukemia lung lesion mouse model mutant novel novel drug class novel therapeutics pharmacokinetics and pharmacodynamics pharmacometrics pre-clinical prevent proteostasis response standard of care tuberculosis drugs tuberculosis treatment

项目摘要

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.

项目概要结核分枝杆菌 (Mtb) 是结核病 (TB) 的病原体，在全球范围内造成更多死亡比任何单一感染因子更有效，但基于利福霉素的护理标准 (SOC) 方案更有效。尽管大剂量利福霉素治疗方案需要6个月的治疗时间，但在全球范围内实施起来却很困难。目前正在试验可能将治疗时间缩短至 4 个月的方案，这些方案和 SOC 都不会使利福霉素耐药或多药耐药 (MDR-) 结核病患者受益，其中约 600,000 名新发结核病患者病例发生于2016年。目前的耐多药结核病治疗方案有毒，需要9-24个月的治疗包含 3 种或更多新药类别的新疗法只能治愈约 50% 的患者。没有预先存在的耐药性可能是变革性的，特别是如果治疗缩短的效果该联盟的总体目标是 (i) 发现和开发新型结核病。针对细菌蛋白质稳态各个方面（协调合成和合成蛋白质的能力）的候选药物降解蛋白质），以及（ii）将这些候选药物组合成能够缩短时间的新型 3 或 4 药物方案药物敏感或 RR-TB 的治疗项目 1-3 将侧重于识别和推进临床前候选药物，每个都针对蛋白质稳态机制的一个组成部分（[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，具有更多的人类如干酪样[坏死]肺部病变、免疫功能低下的裸鼠），项目4，在此描述应用程序，将（1）表征控制细菌活性的暴露-反应关系，耐药性抑制，以及项目 1-3 中出现的先导化合物的毒性（就 TBI-223 而言）再加上 TBI-223，这是一种针对结核病的恶唑烷酮，它已经是结核病赞助的临床前候选药物联盟，(2) 评估干酪样肺部病变对这些暴露-反应关系的影响，以及 (3) 开发包含新兴临床前候选药物最佳剂量的最有效的药物组合来自项目 1-4 并评估其相对于 SOC 在预测性小鼠中缩短治疗的潜力总体目标是开发一种或多种药效优化的、普遍有效的、针对 Mtb 蛋白质稳态的缩短治疗方案。由结核病联盟临床前候选者赞助的稳健、高度协作的结核病药物开发计划项目 1-4 的出现也可能与其他有前途的临床前先导物/候选物相结合，针对蛋白质稳态以外的机制的临床候选药物，从而扩大潜在机会发现转化方案。