UIC: In vitro In vivo Mtb Pharmacology

UIC：体外 体内 Mtb 药理学

• 批准号: 10595581
• 负责人: Scott G. Franzblau
• 金额: $ 96.35万
• 依托单位: GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
• 依托单位国家: 美国
• 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/10595581
• 关键词: 3-Dimensional; ATP phosphohydrolase; Acute; Area; Binding; Binding Proteins; Biochemical; Biological Assay; Chronic; Collaborations; Consultations; Data; Development; Drug resistance; Drug resistant Mycobacteria Tuberculosis; Environment; Evaluation; Generations; Genetic Transcription; Geography; Growth; In Vitro; Infrastructure; Lead; Leadership; Macrophage; Modeling; Molecular Target; Mus; Mutation; Mycobacterium tuberculosis; Pan Genus; Peptide Hydrolases; Pharmacology; Pharmacy facility; Process; Production; Proteins; Regimen; Research; Research Personnel; Resistance; Resources; Ribosomes; Rifampicin resistance; Rifampin; Rifamycins; Running; Safety; Series; Site; Sterilization; Structure; Translational Research; Tuberculosis; Vero Cells; Vertebral column; Work; X-Ray Crystallography; bactericide; college; cytotoxicity; design; drug discovery; drug-sensitive; efficacy evaluation; efficacy testing; experience; genome sequencing; high throughput screening; in vitro Assay; in vitro activity; in vivo; inhibitor; insight; mouse model; mutant; novel; resistant strain; screening; synergism; whole genome

Project Summary/Abstract The central objective of Core B of this CETR is to perform a comprehensive array of mycobacteriological in vitro and in vivo assays, to evaluate anti-Mtb activities broadly and, thereby, serve all Projects 1-4 and Cores A+C within the collaborative context of this CETR. The Core B Leader, Dr. Scott Franzblau, has assembled an experienced research team, which has a long track record of collaboration with the CETR PI/PD and the TB Alliance group, as well as with many other senior CETR investigators. The Core B team is supported by the well-equipped infrastructure of the Institute for Tuberculosis Research (ITR) at UIC’s College of Pharmacy. ITR has established distinctive high-throughput screening (HTS) capabilities for Mtb and has made them available collaboratively to researchers worldwide, which led to the discovery of anti-Mtb leads developed in this CETR. Core B will perform all Mtb screening of active leads/compounds in the CETR, as provided by Projects 1-4, and is organized into three Specific Aims as follows: [AIM 1] in vitro Mtb activity profiling to determine MICs against Mtb under both replicating conditions (MABA) and in non-replicating environments (LORA) and determine general cytotoxicity. By including data from Core A, the in vitro profiles generated in Core B will become part of the CETR lead compound prioritization process. [AIM 2] advanced Mtb activity profiling, aimed at prioritizing the leads from AIM 1 with respect to an extended panel of in vitro assays: selectivity against mini-spectrum, protein binding, activity in macrophage culture, mono-drug resistant Mtb strains, genetically/geographically diverse Mtb strains, and bactericidal activity. The insight evolving from AIM 2 will synergize with safety and ADME/PK data from Core A and the biochemical and target specific assay data from Projects 1-3. [AIM 3] in vivo characterization of Mtb activity in the following mouse models of TB: in vivo preliminary tolerability; capacity to inhibit the growth of Mtb in acute, and bactericidal activity in chronic Mtb infected mice, respectively. Generation of resistant mutants will facilitate mechanism of action studies in the CETR, particularly in Projects 1+3. The activities in Core B’s three Aims will largely run in parallel and be coordinated closely with the other Cores and Projects. Core B will contribute to key aspects of the proposed translational research: the lead identification and optimization driven by Projects 1-3, the regimen development done in Project 4, the drug discovery efforts of Core A, and the IND- enabling work performed in Core C.

项目总结/摘要 本CETR核心B的中心目标是在以下人群中进行一系列全面的分枝杆菌学检测： 体外和体内试验，以广泛评估抗结核杆菌活性，从而服务于所有项目1-4， 核心A+C在本CETR的协作环境中。核心B领导人Scott Franzblau博士 组建了一支经验丰富的研究团队，与CETR PI/PD有着长期的合作记录 和结核病联盟小组，以及许多其他高级CETR调查人员。支持核心B团队 由UIC药学院结核病研究所（ITR）设备齐全的基础设施提供。 ITR已经建立了独特的结核分枝杆菌高通量筛选（HTS）能力， 与世界各地的研究人员合作，这导致了在该CETR中开发的抗Mtb先导物的发现。 核心B将对CETR中的活性先导化合物/化合物进行所有Mt B筛选，如项目1-4所述，以及 [AIM 1]体外Mtb活性谱分析，以确定针对 在复制条件（MABA）和非复制环境（LORA）下的Mtb，并确定一般 细胞毒通过纳入核心A的数据，核心B中生成的体外特征将成为CETR的一部分 领导化合物优先排序流程。[AIM 2]先进的结核病活动分析，旨在确定线索的优先顺序 来自AIM 1的关于体外试验的扩展组：对微光谱的选择性，蛋白结合， 巨噬细胞培养物中的活性，单药耐药Mtb菌株，遗传/地理上不同的Mtb菌株， 和杀菌活性。从AIM 2获得的见解将与核心A的安全性和ADME/PK数据协同作用 以及来自项目1-3的生化和目标特异性测定数据。[AIM Mtb的体内表征 在以下TB小鼠模型中的活性：体内初步耐受性;抑制Mtb生长的能力 在急性和慢性Mtb感染小鼠中的杀菌活性。抗性突变体的产生将 促进CETR的行动机制研究，特别是项目1+3。核心B的三项活动 目标将在很大程度上平行运行，并与其他核心和项目密切协调。核心B将贡献 建议的转化研究的关键方面：铅识别和优化驱动 项目1-3，项目4中完成的方案开发，核心A的药物发现工作，以及IND- 支持在Core C中执行的工作。