Isoprenoid Biosynthesis: A Target for Drugs Against Category A-C Pathogens

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Introduction: The NIAID biodefense research agendas for category A-C agents have identified a need for a broader, more robust arsenal of anti-infective agents. This is important when considered in the light of recent research in genomics and immunology which has greatly eased the task of genetic manipulation of pathogens. Thus, Project II.A.2 arises from the lack of knowledge of key aspects of physiology of Category A-C pathogens which is fundamental to product development. In this project we will concentrate on: 1) A comparison of isopentenyl diphosphate biosynthetic enzymes from a variety of pathogens with the ultimate aim of developing assays for high throughput screening in order to identify compounds that have potential for development into novel therapeutics. 2) the basic biology of cell wall synthesis in Bacillus anthacis, with emphasis on identifying anionic polysaccharides and the "linker-unit" of the organism, polysaccharide biosynthetic pathways and specific drug target identification. Project interactions: This project will be closely integrated with the other projects and Core Facilities described in this proposal. The Project Leaders of this project (II.A.2) are Drs. Dean Crick and Patrick Brennan. Core III.C (Slayden) will provide HTS screening facilities, access to compound libraries and microarrays. Core III.D (Robison) will provide bacterial strains for testing with "hit compounds". We will interact 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 with Project II.A.4 (Schweizer). Our approach of looking for new antibiotic classes will synergize with Schweizers's search for compounds which inhibit efflux pumps. Thus, our hits can be tested for "pumpability" and synergy with compounds that inhibit efflux pumps.