Novel antiobiotic development for biodefense

炭疽杆菌、土拉菌弗朗西斯菌和鼠疫耶尔森菌分别是炭疽、土拉菌病和鼠疫的病原体，由于它们在生物恐怖主义和生物战中的潜在用途，都被列为A类病原体。文献清楚地表明，这三种药物的多重耐药菌株要么是从自然来源中分离出来的，要么可以通过标准的选择过程很容易地选择出来。此外，尽管这三种疾病的野生型菌株都可以用现有的抗生素进行各种治疗，但这些抗生素都不是治疗这些疾病的理想方法，而且通常只有强力霉素适用于一种以上的病原体（炭疽和鼠疫）。因此，开发针对这三种生物体的新治疗剂显然势在必行。在初步工作中，我们已经开发出了烯丙基还原酶（FabI）抑制剂，对炭疽芽孢杆菌和土拉菌以及其他多种病原体都有很强的疗效。此外，甲基萘醌生物合成中的必需酶MenE预计对所有三种生物都是必需的，并且具有非常适合作为所有三种生物的抗生素靶点的特性。基于对这两种酶系统的广泛初步研究，我们建议在这个为期两年的arra资助项目中发现和生物学评估FabI和MenE的先导抑制剂。我们将利用基于结构的分子设计、大型化合物文库的计算机筛选、选定化合物的高通量筛选、合成药物化学、初步体外毒理学评估和初步动物原理证明研究的迭代过程，发现对三种A类病原体（炭疽杆菌、土拉菌和鼠疫杆菌）具有潜在功效的化合物。不同代谢途径的两个靶点将为具有不同特性的先导和后备化合物提供有利的互补潜力。该U01申请的目标是开发一系列先进的广谱抗菌先导化合物，这些化合物在已建立的动物模型中安全、有效且具有口服生物利用度。

Bacillus anthracis, Francisella tularensis and Yersinia pestis, the causative agents for anthrax, tularemia and plague, respectively, are all classed as Category A agents due to their potential use in bioterrorism and biowarfare. Literature clearly demonstrates that multi-drug resistant strains for all three have either been isolated from natural sources, or can be readily selected through standard selection processes. Further, although the wild-type strains of all three are variously treatable with current antibiotics, none of these antibiotics is ideal for treatment of these diseases, and only doxycycline is generally indicated for more than one agent (anthrax and plague). Thus, there is a clear imperative for developing new therapeutic agents against all three organisms. In preliminary work, we have developed inhibitors of the enzyme enoyl reductase, or FabI, that show strong efficacy against both B. anthracis and F. tularensis, as well as a variety of other pathogens. Additionally, MenE, an essential enzyme in menaquinone biosynthesis is predicted to to be essential for all three organisms, and has properties well suited for development as an antibiotic target for all three organisms. Based on extensive preliminary studies with both enzymatic systems, we propose to discover and biologically evaluate lead inhibitors of both FabI and MenE in this two-year ARRA-funded project. We will utilize an iterative process of structure-based molecular design, in silico screening of large compound libraries, high throughput screening of selected compounds, synthetic medicinal chemistry, initial in vitro toxicology evaluation, and initial animal proof of principle studies to discover compounds with potential efficacy against the three Category A pathogens, B. anthracis, F. tularensis and Y. pestis. The two targets in different metabolic pathways will provide advantageous complementary potential for lead and back-up compounds with very different characteristics. The goal of this U01 application is to develop an advanced series of broad spectrum antibacterial lead compounds that are safe, efficacious, and orally bioavailable in established animal models. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page 85 Continuation Format Page