INHIBITION OF SIGNAL PEPTIDASE DEPENDENT SECRETED PROTEINS BY ARYLOMYCIN

arylomycin 对信号肽酶依赖性分泌蛋白的抑制

• 批准号: 7957718
• 负责人: Floyd E. Romesberg
• 金额: $ 0.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957718
• 关键词: Antibiotic Resistance; Antibiotics; Award; Bacteria; Bacterial Proteins; Biological Factors; Biology; Computer Retrieval of Information on Scientific Projects Database; Evolution; Funding; Fungal Genome; Grant; Infection; Institution; Lateral; Lead; Mediating; Mutation; Proteins; Research; Research Personnel; Resistance; Resources; Route; Source; Staphylococcus aureus glutamic acid-specific endopeptidase; Surface; Therapeutic; Type IV Secretion System Pathway; United States National Institutes of Health; Virulence; high throughput screening; in vivo; inhibitor/antagonist; killings; prevent; signal peptidase; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. During the previous award period, we identified bacterial proteins whose inhibition would prevent the evolution of antibiotic resistance-conferring mutations, and also used high-throughput screens to identify lead compounds that inhibit the identified protein targets. We refer to the compounds as ?antibiotics? (because they should kill bacteria in the context of an infection) but also as ?achaogens? (because they should inhibit the evolution of resistance). Such compounds might have important uses as a co-therapy with traditional antibiotics or on their own. In this Renewal Application, we seek funds to further evaluate these lead compounds biochemically and begin to define therapeutic applications where they may be useful. Specifically we will focus on defining the ability of our lead compounds to inhibit mutation and also to kill bacteria in the context of several important infections. We also propose the extension of the achaogen concept to include inhibitors of lateral transfer, another major route by which bacteria evolve resistance to antibiotics. Our preliminary results include the synthesis and identification of several small molecules that inhibit lateral transfer via the inhibition of type I signal peptidase (SPase), which is required for the assembly of the type IV secretion systems that mediate lateral transfer. We have shown that a class of penems inhibit SPase and lateral transfer in vivo, as does a class of natural products known as the arylomycins. Because SPase is also required for the export of most surface displayed or secreted proteins, its inhibition, like that of RecA, should dramatically reduce bacterial virulence. We thus also seek funds to optimize the penem and arylomycin compounds as antibiotic/achaogens. The major deliverables of the proposed research are thus at least one class of antibiotic/achaogen that acts via the inhibition of RecA, and one that acts via the inhibition of SPase.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在上一个奖项期间，我们确定了细菌蛋白质，其抑制作用可以防止抗生素耐药性突变的演变，并使用高通量筛选来确定抑制所确定的蛋白质靶标的先导化合物。 我们把这些化合物称为？抗生素吗（因为它们应该在感染的情况下杀死细菌），但也作为？achaogens？（因为它们应该抑制抗性的进化）。 这些化合物可能作为传统抗生素的联合治疗或单独使用具有重要用途。 在此更新申请中，我们寻求资金以进一步评估这些先导化合物的生物化学性质，并开始确定其可能有用的治疗应用。 具体来说，我们将重点关注我们的先导化合物抑制突变的能力，以及在几种重要感染的背景下杀死细菌的能力。 我们还建议扩展achaogen的概念，包括抑制剂的横向转移，另一个主要途径，细菌进化耐药性的抗生素。 我们的初步结果包括几个小分子的合成和鉴定，通过抑制I型信号肽酶（SPase），这是必要的IV型分泌系统，介导的横向转移的组装抑制横向转移。 我们已经证明，一类青霉烯类抑制SPase和侧向转移在体内，作为一类天然产物被称为芳基霉素。 由于SPase也是大多数表面展示或分泌蛋白的输出所必需的，因此它的抑制作用与RecA的抑制作用一样，应该会显著降低细菌的毒力。 因此，我们还寻求资金来优化作为抗生素/achaogens的青霉烯和芳基霉素化合物。 因此，拟议研究的主要成果是至少一类通过抑制RecA发挥作用的抗生素/achaogen，以及一类通过抑制SPase发挥作用的抗生素/achaogen。