UIC: In vitro In vivo Mtb Pharmacology

UIC：体外 体内 Mtb 药理学

• 批准号: 10388411
• 负责人: Scott G. Franzblau
• 金额: $ 85.09万
• 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/10388411
• 关键词: 3-Dimensional; ATP phosphohydrolase; Acute; Area; Back; 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; Institutes; Lead; Leadership; 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; Rifamycins; Running; Safety; Series; Site; Sterilization; Structure; Translational Research; Tuberculosis; Vero Cells; Vertebral column; Work; X-Ray Crystallography; bactericide; base; college; cytotoxicity; design; drug discovery; drug-sensitive; efficacy testing; experience; genome sequencing; high throughput screening; in vitro Assay; in vitro activity; in vivo; inhibitor; insight; macrophage; mouse model; mutant; novel; resistant strain; screening; 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.

项目摘要/摘要 这个CETR的核心B的中心目标是执行一系列全面的分支杆菌 体外和体内检测，以广泛评估抗结核分枝杆菌的活性，从而服务于所有项目1-4和 在本CETR的协作范围内的核心A+C。核心B领导人Scott Franzblau博士已经 组建了一支经验丰富的研究小组，该小组与经济、社会和文化权利中心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CETR高级调查人员。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已经为结核分枝杆菌建立了独特的高通量筛选(HTS)能力，并已使其可用 与世界各地的研究人员合作，导致在这项CETR中发现了抗结核分枝杆菌的线索。 核心B将按照项目1-4的规定，对CETR中的活性铅/化合物进行所有MTB筛选，以及 被组织为三个特定的目标如下：[目标1]体外结核分枝杆菌活性分析，以确定MIC 在复制条件(MABA)和非复制环境(LORA)下的MTB，并确定一般 细胞毒性。通过包括来自核心A的数据，在核心B中产生的体外图谱将成为CETR的一部分 领导化合物的优先顺序流程。[目标2]高级MTB活动概况，旨在确定销售线索的优先顺序 来自AIM 1相对于一组扩展的体外检测：对微光谱的选择性，蛋白质结合， 巨噬细胞培养中的活性，耐单一药物的结核分枝杆菌菌株，遗传/地理多样性的结核分枝杆菌菌株， 和杀菌活性。从AIM 2发展而来的洞察力将与来自Core A的SAFE和ADME/PK数据协同 以及来自项目1-3的生化和靶标特异性分析数据。[目的3]结核分枝杆菌的体内特性 以下小鼠结核模型的活性：体内初步耐受性；抑制结核分枝杆菌生长的能力 在急性和慢性结核分枝杆菌感染小鼠中分别具有杀菌活性。抗药性突变体的产生将 促进经济、社会和文化权利中心的行动机制研究，特别是在项目1+3中。核心B的三项活动 AIMS将在很大程度上并行运行，并与其他核心和项目密切协调。核心B将做出贡献 到提议的翻译研究的关键方面：由以下驱动的领导识别和优化 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- 支持在核心C中执行的工作。