Introduction: The NIAID biodefense research agendas for category A-C agents have identified a need for abroader, more robust arsenal of anti-infective agents. This is important when considered in the light ofrecent research in genomics and immunology which has greatly eased the task of genetic manipulation ofpathogens. Thus, Project II.A.2 arises from the lack of knowledge of key aspects of physiology of CategoryA-C pathogens which is fundamental to product development. In this project we will concentrate on: 1) Acomparison of isopentenyl diphosphate biosynthetic enzymes from a variety of pathogens with the ultimateaim of developing assays for high throughput screening in order to identify compounds that have potential fordevelopment into novel therapeutics. 2) the basic biology of cell wall synthesis in Bacillus anthacis, withemphasis on identifying anionic polysaccharides and the 'linker-unit' of the organism, polysaccharidebiosynthetic pathways and specific drug target identification.Project interactions: This project will be closely integrated with the other projects and Core Facilitiesdescribed in this proposal. The Project Leaders of this project (II.A.2) are Drs. Dean Crick and PatrickBrennan. Core III.C (Slayden) will provide HTS screening facilities, access to compound libraries andmicroarrays. Core III.D (Robison) will provide bacterial strains for testing with 'hit compounds'. We willinteract with Project II.C (Vasil) to test efficacy of compounds in intracellular models and Project II A3(Belisle) to test compound efficacy against Francisella tularensis. There will also be close interactions withProject II.A.4 (Schweizer). Our approach of looking for new antibiotic classes will synergize withSchweizers's search for compounds which inhibit efflux pumps. Thus, our hits can be tested for'pumpability' and synergy with compounds that inhibit efflux pumps.
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