Broad Spectrum Agents Against Cat A Bacterial Pathogens

生物恐怖分子的武器库可能包括广泛的细菌物种，包括A类病原体鼠疫耶尔森氏菌(鼠疫)(革兰氏阴性菌)和炭疽杆菌(炭疽杆菌)(革兰氏阳性菌)。广谱抗生素可能是最有价值的生物防御药物，因为即使在没有确凿的物种诊断鉴定的情况下，这些药物也可以快速使用，并且可以更有效地储存，成本更低。这项建议的总体目标是寻找新的抗菌剂，用于对广泛的物种和广泛的耐药机制进行生物防御。我们将专注于一个新的化学系列，它有效地抑制UDP-GlcNAc烯醇式丙酮酸转移酶(EPT)，EPT是一种重要的、广泛保守的细菌特异性酶，催化肽聚糖合成的第一步。我们将通过重点应用合理的、基于结构的药物设计来优化这一抑制剂系列，以产生在 体内感染模型。具体目标是(1)领导验证：优化 喹恶啉抑制剂对鼠疫耶尔森氏菌和炭疽杆菌的抑制作用；(2)体外/抗菌先导优化： 展示鼠疫杆菌和炭疽杆菌天然和工程替代物的靶标特异性和生长或活性抑制，以及(3)目标3.体内先导优化：在动物感染模型中展示EPT抑制剂对替代优先病原体的体内疗效，并优化临床前候选者的活性。

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.