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种类，包括A类病原体鼠疫耶尔森氏菌（鼠疫），一种革兰氏阴性菌，和炭疽芽孢杆菌（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。本提案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。我们将专注于一个新的化学系列，有效抑制UDP-GlcNAc烯醇丙酮基转移酶（EPT），这是一种重要的，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，以产生对肿瘤有效的先导化合物

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.