DISCOVERY AND DEVELOPMENT OF BIODEFENSE ANTIMICROBIALS

说明（申请人提供）：恐怖组织利用微生物作为美国生物战剂的威胁是通过美国邮件故意使平民接触炭疽杆菌孢子。由于新的耐药性细菌菌株的出现以及缺乏对潜在的生物恐怖剂特别有效的抗生素，需要开发新的抗菌治疗剂。该提案通过开发用于治疗NIAID A类细菌引起的感染的新的临床前候选药物来解决这一需求。从SRI International的化学库中对三种NIAID A类细菌进行了一组重点化合物的初步筛选，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）通过筛选SRI内部的化学库，针对三种NIAID A类细菌，确定一组活性先导化合物-SRI已经成功地开始了这一活动。(2)基于目标1中确定的先导化合物，设计和合成一组具有增强的抗微生物活性的改性化合物。根据抗菌活性确定1-5种潜在的候选药物，并筛选候选药物的毒性、代谢稳定性和口服生物利用度。具有最佳生物学特性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/开发项目将产生重要的初步结果，用于提出由主要研究者（PI）及其SRI同事进行的关于发现和开发新抗菌药物的更大R 01研究。

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.