UIC: In vitro In vivo Mtb Pharmacology

项目总结/文摘

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.