New Broad-Acting Cell Wall Antibiotics for Biodefense

描述（由申请人提供）：生物恐怖武器库可能包括广泛的细菌种类，包括A类病原体鼠疫耶尔森氏菌（鼠疫），革兰氏阴性物种，和炭疽芽孢杆菌（炭疽），革兰氏阳性物种。广谱抗生素可能是最有价值的生物防御药物，因为这些药物即使在没有物种确认诊断鉴定的情况下也可以快速使用，并且可以以更低的成本更有效地储存。本应用程序的总体目标是确定新的抗菌剂，用于生物防御广泛的物种和广泛的耐药机制。在第一阶段，我们将重点研究一种新的化学系列，它能有效抑制UDP-GlcNAc烯醇丙酮基转移酶（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。具体目的是：(1)优化新抑制剂对鼠疫杆菌（Yp）和炭疽芽孢杆菌（Ba）的效价；(2)证明Yp和Ba的天然和工程代物的靶向特异性和抑制生长或活力；(3)在感染动物模型中证明EPT抑制剂对Yp和Ba代物的体内有效性，并确定先导化合物的体外ADMET谱。在II期，我们将优化体内验证的药物，使其成为临床候选药物。

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.