Hexameric PBGS as a Bioterrorism Defense

描述（由申请人提供）：国防需要开发新的战略来打击潜在的生物恐怖主义制剂。这一战略的目标之一是开发新的抗微生物剂。Jaffe实验室已经确定了六聚体-八聚体平衡作为四吡咯生物合成中的关键酶--胆色素原合酶（PBGS）的变构控制的结构基础。无活性六聚体的捕获被提议作为发现针对NIAID优先病原体类鼻疽伯克霍尔德氏菌、梅菲布氏菌、鼻疽伯克霍尔德氏菌、普氏立克次体、霍乱弧菌和小肠结肠炎耶尔森氏菌的新抗菌剂的基础。 该探索性建议的目的是：1）构建来自这些病原体的PBGS的六聚体的蛋白质结构模型; 2）使用计算对接程序来发现将优先结合并稳定六聚体的分子;以及3）测试所鉴定的分子抑制这些病原体的PBGS而不抑制人PBGS的能力。 本提案描述了一个高风险、高影响的勘探项目。拟议研究的成功将为物种选择性抗生素的开发建立一个急需的新目标，可用于对NIAID优先病原体的生物防御。

DESCRIPTION (provided by applicant): National defense requires development of novel strategies to combat potential bio-terrorism agents. One target of this strategy is the development of new antimicrobial agents. The Jaffe laboratory has identified a hexamer-octamer equilibrium as the structural basis for allosteric control of a key enzyme in tetrapyrrole biosynthesis, porphobilinogen synthase (PBGS). Trapping of the inactive hexamer is proposed as a basis for discovery of new antimicrobials directed against the NIAID priority pathogens Burkholderia pseudomallei, Brucella mefitensis, Burkholderia mallei, Rickettsia prowazekii, Vibrio cholerae, and Yersinia enterocolitica. The aims of this exploratory proposal are: 1) To build protein structure models for hexamers of PBGS from these pathogens; 2) To use computational docking procedures to discover molecules that will preferentially bind to and stabilize the hexamer; and 3) To test the identified molecules for their ability to inhibit the PBGS of these pathogens while not inhibiting human PBGS. The current proposal describes a high risk - high impact exploratory project. Success of the proposed studies will establish a much needed new target for species selective antibiotic development that can be applied to bio-defense against NIAID priority pathogens.