New Broad-Acting Cell Wall Antibiotics for Biodefense

描述（由申请人提供）：生物恐怖分子的武器库可能包括广谱细菌物种，包括A类病原体鼠疫耶尔森氏菌（鼠疫）（革兰氏阴性物种）和炭疽杆菌（炭疽）（革兰氏阳性物种）。广谱抗生素可能是生物防御中最有价值的，因为即使在没有对物种进行确证性诊断鉴定的情况下，这些制剂也可以迅速使用，并且可以更有效和更低成本地储存。本申请的总体目标是鉴定可用于针对广谱物种和广泛耐药机制的生物防御的新抗菌剂。在第一阶段，我们将集中在一个新的化学系列，有效地抑制UDP-GlcNAc烯醇化酶（EPT），一个必不可少的，广泛保守的，细菌特异性酶催化肽聚糖合成的第一个关键步骤。我们将通过集中应用合理的和基于结构的药物设计来优化该抑制剂系列，以产生在体内感染模型中有效的先导化合物。具体目标是：（1）优化新的EPT抑制剂对Y.鼠疫菌（Yp）和B.炭疽菌（Ba）;（2）证明靶特异性和对Yp和Ba的天然和工程化替代物的生长或活力的抑制;和（3）证明EPT抑制剂在感染动物模型中针对Yp和Ba替代物的体内功效以及确定先导化合物的体外ADMET谱。在第二阶段，我们将优化体内验证的导致临床候选人的状态。

DESCRIPTION (provided by applicant): 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 application is to identify new antibacterial agents useful for biodefense against a broad spectrum of species and a wide range of drug resistance mechanisms. In Phase I, 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 aims are to (1) optimize the potency of the new inhibitors on EPT from Y. pestis (Yp) and B. anthracis (Ba); (2) demonstrate target specificity and inhibition of growth or viability of natural and engineered surrogates of Yp and Ba; and (3) demonstrate in vivo efficacy of EPT inhibitors against Yp and Ba surrogates in animal models of infection as well as determine in vitro ADMET profiles for the lead compounds. In Phase II, we will optimize an in vivo validated lead to the status of a clinical candidate.