Antibiotics targeting siderophore receptors

针对铁载体受体的抗生素

• 批准号: 9206983
• 负责人: Valerie C. Pierre
• 金额: $ 19.03万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206983
• 关键词: Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Behavior; Biological Assay; Blood; Cells; Centers for Disease Control and Prevention (U.S.); Cerebrospinal Fluid; Development; Enterobacter; Enterobacteriaceae; Enterobacteriaceae Infections; Enterobactin; Escherichia coli; Extended-spectrum β-lactamase; Family; Goals; Growth; Health; Healthcare; Human; Human body; In Vitro; Infection; Iron; Iron Chelating Agents; Klebsiella; Klebsiella pneumonia bacterium; Mammalian Cell; Membrane; Metabolic; Outcome; Particulate; Pharmaceutical Preparations; Prevalence; Property; Public Health; Research; Resistance; Siderophores; Skin; Structure; System; Toxic effect; United States; Urine; Virulence; Virulence Factors; Virulent; Work; aerobactin; bacterial resistance; bactericide; base; carbapenem resistance; carbapenem-resistant Enterobacteriaceae; cost; disorder prevention; fighting; innovation; macromolecule; microorganism; nanoparticle; novel; novel therapeutics; pathogen; public health relevance; receptor; resistant strain; siderophore receptors; uptake

 DESCRIPTION (provided by applicant): Antibiotic-resistant Enterobacteriaceae, including carbapenem-resistant and extended spectrum β-lactamase producing Klebsiella spp., Escherichia coli, and Enterobacter spp. are considered by the Centers for Disease Control and Prevention (CDC) to be urgent and serious health threats to the United States. Our long term goal is to develop and evaluate novel antibiotics for the Enterobacteriaceae. We will attain our goal with nanoparticle and dendrimeric siderophore plugs. Siderophores are powerful iron chelators synthesized and excreted by microorganisms to sequester and return the iron needed for their growth. All Enterobacteriaceae rely primarily on the siderophore enterobactin for their iron acquisition. Because iron is a limiting factor in bacterial growth in the human body (includin on skin and in blood, urine and cerebrospinal fluid), this siderophore has long been established as a virulence factor for all Enterobacteriaceae. Increased expression of the outer-membrane siderophore receptors for enterobactin, FepA, has been repeatedly observed during infection with all the virulent strains of the Enterobacteriaceae. Our central hypothesis is that siderophore anchors that block the siderophore transport systems of the Enterobacteriaceae will significantly reduce the virulence of the bacteria by starving it. The overall objective of this application is t synthesize and evaluate a new family of enterobactin plugs as antibiotics for the treatment of the Enterobacteriaceae. The rationale for the proposed research is that the availability of more powerful antibiotics and antibiotics with novel modes of actions is necessary to treat increasingly prevalent bacterial pathogens that are resistant to current drugs. We plan to accomplish our objectives by pursuing the following Specific Aims: 1) Synthesize enterobactin plugs that block the FepA receptor; and 2) Evaluate the potential of enterobactin plugs as antibiotics. This research is significant because it aims to develop a new class of antibiotics that exploits a novel mechanism of action and that targets microorganisms, which present urgent and serious threats, that are resistant to current classes of antibiotics. Our approach is innovative because we are exploiting the siderophore receptor itself as a target for antibiotics with novel mechanisms of actions. The transporters involved in the uptake of iron themselves have not yet been evaluated as targets for antibiotics.

 描述（由申请人提供）：疾病控制和预防中心 (CDC) 认为抗生素耐药性肠杆菌科细菌，包括耐碳青霉烯类和产生广谱 β-内酰胺酶的克雷伯菌属、大肠杆菌和肠杆菌属是紧迫的。我们的长期目标是开发和评估针对肠杆菌科的新型抗生素。我们将实现我们的目标。铁载体是由微生物合成和分泌的强大铁螯合剂，用于隔离和返回其生长所需的铁，所有肠杆菌主要依赖铁载体肠杆菌素获取铁，因为铁是细菌生长的限制因素。在人体中（包括皮肤以及血液、尿液和脑脊液中），这种铁载体早已被确定为所有肠杆菌科细菌的毒力因子。在感染所有肠杆菌科细菌的过程中，反复观察到肠杆菌素外膜铁载体表达增加。我们的中心假设是铁载体。 阻断肠杆菌科的铁载体运输系统的锚将通过饥饿来显着降低细菌的毒力。该应用的总体目标是合成和评估作为治疗肠杆菌科的抗生素的新肠杆菌素家族。拟议的研究表明，有必要提供更强大的抗生素和具有新颖作用方式的抗生素来治疗越来越多的疾病 对现有药物具有抗药性的流行细菌病原体我们计划通过实现以下具体目标来实现我们的目标：1）合成阻断 FepA ​​受体的肠杆菌素塞；2）评估肠杆菌素塞作为抗生素的潜力。因为它的目的是开发一类新的抗生素，利用一种新的 我们的方法是创新的，因为我们正在利用铁载体受体本身作为具有新颖作用机制的抗生素的靶标。铁的吸收本身尚未被评估为抗生素的目标。