DISCOVERY AND DEVELOPMENT OF BIODEFENSE ANTIMICROBIALS

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DESCRIPTION (provided by applicant): The threat of terrorist organizations' use of microorganisms as biowarfare agents in the United States was realized with the deliberate exposure of the civilian population to Bacillus anthacis spores through the U.S. mail. Because of the emergence of new and antibiotic-resistant strains of bacteria and lack of antibiotics that are specifically effective against potential bioterrorism agents, new antibacterial therapeutics need to be developed. This proposal addresses that need by developing new preclinical drug candidates for the treatment of infections caused by NIAID Category A bacteria. Initial screening of a focused set of compounds from SRI International's chemical library against three NIAID Category A bacteria identified eight compounds with promising antimicrobial activity. The Specific Aims of this proposal are to (1) identify a set of active lead compounds by screening SRI's in-house chemical library against three NIAID Class A bacteria--activity that SRI has already begun successfully. (2) Design and synthesize a set of modified compounds based on the identified leads from Aim 1 with enhanced antimicrobial activity. Identify 1-5 potential drug candidate(s) on the basis of their antimicrobial activity, and screen the candidates for toxicity, metabolic stability, and oral bioavailability. Candidate compounds with the best biological profiles will be produced on a scale that will be sufficient for preclinical trials. This R21 pilot/developmental project will generate significant preliminary results to use in proposing a larger R01 study on the discovery and development of new antimicrobial agents by the Principal Investigator (PI) and his SRI colleagues.