DEVELOPMENT OF A REPRESSOR BASED SCREEN FOR ANTIBIOTICS

描述（改编自申请人的摘要）：本提案的目的是 基于两者的共同特征开发技术平台 革兰氏阳性和革兰氏阴性病原体：铁的绝对需求。 PI将重点放在铁激活的阻遏物上，这些阻遏物控制着 铁的吸收和储存基因，除了许多毒力基因， 一种新型抗生素的靶点这种方法的有效性一直是 使用白喉毒素阻遏物DtxR证明。不依赖铁 DtxR的超阻遏突变体已经利用最近的 基因筛查这些突变体被用来产生部分二倍体 在结核分枝杆菌中， 小鼠攻击实验。PI建议扩大这一方法和目标 IdeR在M.结核分枝杆菌和IdeRa。avium铁的影响独立 这些基因中的突变将在M.结核 和M. avium如果这些突变体显示出改变的活力，那么IdeR/IdeRa 基因将被用来修改和发展PSTD系统作为一个特定的屏幕 用于抗分枝杆菌化合物。 拟定商业应用： 应用现有的一级分析法作为鉴定铅抗菌剂的工具 用于治疗抗生素抗性细菌感染的化合物。 潜力 开发抗生素作为治疗多种微生物病原体感染的最后手段 包括作为主要疗法或在组合疗法中的应用， 提高现有抗生素的疗效。 有可能实现很大比例的 每年60亿美元的抗菌药物市场。

DESCRIPTION (Adapted from Applicant's Abstract): This proposal's aim is to develop a technology platform based upon a common characteristic of both Gram-positive and Gram-negative pathogens: an absolute requirement for iron. The PI has focused on iron-activated repressors, which control the expression of iron uptake and storage genes in addition to many virulence genes, as targets for a new class of antibiotics. This approach's validity has been demonstrated using the diphtheria toxin repressor, DtxR. Iron independent hyper-repressor mutants of DtxR have been isolated utilizing a recently published genetic screen. These mutants were used to generate partial diploids in Mycobacterium tuberculosis that resulted in the attenuation of virulence in mouse challenge experiments. The PI proposes to expand this approach and target IdeR in M. tuberculosis and IdeRa in M. avium. The effects of iron independent mutations in these genes will be assessed in growth assays of M. tuberculosis and M. avium. If these mutants display altered viability then the IdeR/IdeRa genes will be used to modify and develop the PSTD system as a specific screen for anti-mycobacterial compounds. PROPOSED COMMERCIAL APPLICATION: Application of existing primary assay as a tool for identification of lead anti-microbial compoundsfor the treatment of antibiotic resistant bacterial infections. Potential to develop antibiotics of last resort for infection by a number of microbial pathogens including application as a primary therapy or in combinatorial therapy to enhance enhance efficacy of existing antibiotics. Potential to achieve large percentage of annual $US6 billion antimicrobial drug market.