Globally, resistance to antimicrobial agents is on the rise, and new antimicrobial agents are urgently needed to counter severe human pathogens such as malaria and resistant bacteria. Translational efforts towards drug development depend on high-throughput screening of small molecule compound libraries, in order to identify new molecules that inhibit microbial cellular function or toxin action. These """"""""hits,"""""""" identified by screening, are lead compounds that may be the backbone of new antimicrobial compound development. A key component of such screening efforts is purification of large amounts of the microbial enzymatic target that is to be screened. Our laboratories have already successfully implemented screens against two such targets and are developing assays for several additional microbial targets. To this end, support is requested for a GE AktaExplorer liquid chromatography system. With multiple automated features (such as pH and column scouting), this system is designed for rapid development and optimization of biomolecular purification. Additional components include fraction collection (on the basis of built-in UV, pH, time, or conductivity monitoring), autosampling, and straightforward operational software that would provide significant flexibility for multiple users. Acquisition of this system would significantly aid high- throughput screening efforts that are currently limited by current chromatographic equipment. NIH funded research projects to be supported by this shared instrument include the following: (1) drug development for malaria and other human parasitic diseases (Beverley, Odom, Sibley, and Tolia);(2) bacterial anti-toxin drug development (Haslam);(3) anti-viral drug development (French);and receptor ligand interactions (Bu, Schwartz). The project brings together several NIH-funded investigators with similar needs for a high-end protein purification system. All of the investigators are in the Departments of Pediatrics and Molecular Microbiology, including respective Chairs of both Departments. All laboratories are within the McDonnell Pediatric Research Building, where the AKTA system will be housed. As principal investigator, Dr. Odom will be principally responsible for overseeing the equipment. An Advisory Committee comprised of major users has been convened to oversee usage and maintenance of the apparatus. There is strong institutional and departmental commitment to housing and maintaining the AKTA system. To that end, the Department of Pediatrics has committed to providing funds for maintenance and service contracts, ensuring the Akta system will function in peak form for at least the next 10 to 15 years in ongoing support of NIH-funded research at Washington University.
A collaborative group of seven NIH-supported investigators from the Departments of Pediatrics and Molecular Microbiology at Washington University School of Medicine request funding for the purchase of an ATKA Explorer 100 Air liquid chromatography system. Each of the investigators requires highly purified proteins to answer basic questions about human disease or to perform high-throughput screening (HTS) of small molecule inhibitors that hold potential as novel therapies against parasitic, viral, and toxin-mediated diseases. As such, the AKTA Explorer will directly facilitate the research undertaken by each investigator and contribute directly to human health.
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