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）：恐怖组织将微生物用作美国生物生物的威胁是通过美国邮寄的平民汇总到bacillus anthacis孢子的情况下实现的。由于细菌的新型和抗生素抗性菌株以及缺乏针对潜在的生物恐怖剂有效的抗生素，因此需要开发新的抗菌治疗剂。该提案通过开发新的临床前药物来治疗niAID类别A细菌引起的感染来解决。对三个NIAID类别A细菌的最初筛选一组重点的化合物，鉴定出具有有希望的抗菌活性的八种化合物。该提案的具体目的是（1）通过筛选SRI的内部化学文库来确定一组活跃的铅化合物，以针对三种NIAID A类细菌进行筛查 - SRI已经成功地开始了活动。 （2）基于AIM 1的鉴定铅具有增强的抗菌活性，设计和合成一组修改的化合物。根据其抗菌活性确定1-5个潜在的候选药物，并筛选候选毒性，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将以足以进行临床前试验的规模生产。该R21试点/发展项目将产生重要的初步结果，以提出对主要研究者（PI）及其SRI同事对新抗微生物剂的发现和开发进行更大的R01研究。