Metal Repressor Targets and Peptide Activators

描述(申请人提供)：治疗变得越来越困难 细菌感染，如肺结核、葡萄球菌和链球菌 由于出现了多个耐药菌株。合理用药 设计可能会被证明对开发新的抗生素制剂来说是无价的。进阶 微生物解决方案公司(AMS)开发新型抗菌剂 以金属离子激活的转录抑制物为靶点的药物。战略 AMS利用已知的遗传、生化和结构信息 关于这一类的原型抑制物，白喉毒素抑制物， (DtxR)和从多个不同病原菌中克隆的遗传同源物 细菌开发特定的抗微生物药物。 铁的监管不仅对入侵和建立 感染剂还能使其在宿主体内存活。铁依赖症 抑制子DtxR最初是从白喉棒状杆菌克隆的，它与 毒力基因上游的特定操纵子序列，控制着 表达白喉毒素、铁载体和 血红素加氧酶。因此，控制毒力基因的表达 通过激活这些金属依赖的调节器可以减少 病原体的生存能力。这项提案的具体目标是从 要定义目标阻滞器的临界面，它控制 铁依赖表型，并产生第二代多肽激活剂。 建议的商业应用：不可用

DESCRIPTION (provided by applicant): It is becoming more difficult to treat bacterial infections such as, tuberculosis, staphylococcus, and streptococcus due to the emergence of multiple antibiotic-resistant strains. Rational drug design may prove invaluable for developing new antibiotic agents. Advanced Microbial Solutions Corporation (AMS) developing a new class of anti-microbial agents targeted at metal ion-activated transcriptional repressors. The strategy utilized by AMS uses genetic, biochemical and structural information known about the prototypical repressor of this class, Diphtheria Toxin Repressor, (DtxR) and genetic homologues cloned from a number of different pathogenic bacteria to develop specific anti-microbial drugs. Iron regulation is critical for not only invasion and establishment of the infectious agent but also its survival in the host. The iron-dependent repressor, DtxR, originally cloned from Corynebacterium diphtheriae, binds to specific operator sequences upstream of virulence genes, which control the expression of such products as diphtheria toxin, siderophores and heme-oxygenase. Therefore, controlling the expression of virulence genes through the activation of these metal-dependent regulators can reduce a pathogens ability to survive. The specific aims of this proposal are to begin to define the critical surfaces of the target repressors, which control the iron-dependent phenotype, and to generate second-generation peptide activators. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE