Broad Spectrum Agents Against Cat A Bacterial Pathogens

针对 A 类细菌病原体的广谱药剂

• 批准号: 6998690
• 负责人: Ania Knap
• 金额: $ 145.07万
• 依托单位: MAXTHERA, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998690
• 关键词: Bacillus anthracis; X ray crystallography; Yersinia pestis; Yersinia pestis disease; alkyltransferase; anthrax; anthrax toxin; antibacterial agents; bioterrorism /chemical warfare; chemical synthesis; drug design /synthesis /production; drug resistance; drug screening /evaluation; enzyme inhibitors; mass spectrometry; peptidoglycan; pharmacokinetics; polymerase chain reaction; quinoxalines

A bioterrorist arsenal is likely to include a broad spectrum of bacterial species including the Category A pathogens Yersinia pestis (plague), a Gram-negative species, and Bacillus anthracis (anthrax), a Gram-positive species. Broad-spectrum antibiotics are potentially the most valuable for biodefense because these agents can be used quickly even in the absence of confirmatory diagnostic identification of species and can be stockpiled more efficiently and at lower cost. The overall goal of this proposal is to identify new antibacterial agents useful for biodefense against a broad spectrum of species and a wide range of drug resistance mechanisms. We will focus on a novel chemical series that potently inhibits UDP-GlcNAc enolpyruvyl transferase (EPT), an essential, broadly conserved, bacterial-specific enzyme catalyzing the first committed step in peptidoglycan synthesis. We will optimize this inhibitor series through a focused application of rational and structure-based drug design to generate lead compounds that are effective in an in vivo infection model. The specific objectives are to (1) Lead validation: Optimize the potency of quinoxaline inhibitors on Y. pestis and B. anthracis EPT.; (2) In vitro/antimicrobial lead optimization: Demonstrate target specificity and inhibition of growth or viability of natural and engineered surrogates of Y. pestis and B. anthracis', and (3) Objective 3. In vivo lead optimization: Demonstrate in vivo efficacy of EPT inhibitors against surrogate priority pathogens in animal models of infection and optimize activity for preclinical candidate.

生物恐怖主义武器库可能包括种类繁多的细菌种类，包括病原体耶尔森氏菌（Pestis yersinia pestis（PESTIS），一种革兰氏阴性物种和炭疽芽孢杆菌（炭疽菌）（炭疽病），革兰氏阳性物种。广谱抗生素可能是生物污染最有价值的，因为即使在没有验证性诊断性鉴定物种的情况下，这些药物也可以迅速使用，并且可以更有效地以较低的成本储存。该提案的总体目标是确定针对多种物种和广泛的耐药性机制有用的新抗菌剂。我们将重点放在一个新型的化学系列上，该系列有效抑制UDP-GLCNAC Enolpyruvyl转移酶（EPT），这是一种必不可少的，广泛的，细菌特异性的酶，催化了肽聚糖合成的第一步。我们将通过集中应用基于理性和结构的药物设计来优化该抑制剂系列，以生成有效的铅化合物 体内感染模型。具体目标是（1）潜在客户验证：优化 Y. Pestis和B.炭疽芽孢杆菌EPT上的quinoxaline抑制剂； （2）体外/抗菌铅优化： 证明靶特异性和抑制Y. pestis和B.炭疽病的天然和工程替代物的生长或生存能力的抑制作用，以及（3）目标3。体内铅优化：在体内抑制剂对替代品的体内抑制剂在动物模型中的体内抑制剂在体内抑制剂的效率，以使预先促进候选动物的活性和优化活性。