Hexameric PBGS as a Bioterrorism Defense

描述(由申请者提供)：国防需要开发新的战略来打击潜在的生物恐怖主义特工。这一战略的目标之一是开发新的抗菌剂。Jaffe实验室已经确定六聚体-八聚体平衡是四吡咯生物合成中的关键酶--胆红素原合成酶(PBGS)变构控制的结构基础。捕捉失活的六聚体被认为是发现针对NIAID优先病原体假性伯克霍尔德氏菌、梅菲氏布鲁氏菌、马利氏伯克霍尔德氏菌、普氏立克次体、霍乱弧菌和小肠结肠炎耶尔森菌的新的抗菌剂的基础。 这项探索性建议的目的是：1)建立来自这些病原体的PBGS六聚体的蛋白质结构模型；2)使用计算对接程序来发现优先与六聚体结合并稳定该六聚体的分子；以及3)测试已识别的分子在不抑制人类PBGS的同时抑制这些病原体的PBGS的能力。 目前的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开发建立一个亟需的新目标，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.