DISCOVERY AND DEVELOPMENT OF BIODEFENSE ANTIMICROBIALS

生物防御抗菌药物的发现和开发

• 批准号: 6803214
• 负责人: MARY J TANGA
• 金额: $ 40.73万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2006-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803214
• 关键词: Bacillus anthracis; Francisella tularensis; Yersinia pestis; antibacterial agents; bioterrorism /chemical warfare; drug design /synthesis /production; drug discovery /isolation; drug screening /evaluation; microorganism culture

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.

描述（由申请人提供）：在美国，恐怖组织利用微生物作为生物战剂的威胁是通过美国邮件故意使平民接触炭疽芽孢杆菌孢子而实现的。由于新的抗生素耐药细菌菌株的出现，并且缺乏专门有效对抗潜在生物恐怖主义制剂的抗生素，因此需要开发新的抗菌疗法。该提案通过开发用于治疗 NIAID A 类细菌引起的感染的新临床前候选药物来满足这一需求。对 SRI International 化学库中针对三种 NIAID A 类细菌的一组重点化合物进行初步筛选，确定了八种具有良好抗菌活性的化合物。该提案的具体目标是 (1) 通过针对三种 NIAID A 类细菌筛选 SRI 的内部化学库来确定一组活性先导化合物，SRI 已经成功开始了这种活性。 (2) 基于目标 1 中确定的先导化合物，设计并合成一组具有增强抗菌活性的修饰化合物。根据抗菌活性鉴定 1-5 种潜在候选药物，并筛选候选药物的毒性、代谢稳定性和口服生物利用度。具有最佳生物学特征的候选化合物的生产规模将足以进行临床前试验。这个 R21 试点/开发项目将产生重要的初步结果，用于提议由首席研究员 (PI) 和他的 SRI 同事进行更大规模的 R01 研究，以发现和开发新的抗菌药物。