Antibiotics targeting siderophore receptors

 描述(申请人提供)：耐抗生素肠杆菌科，包括耐碳青霉烯类和产超广谱β-内酰胺酶的克雷伯氏菌、大肠杆菌和肠杆菌属。被疾病控制和预防中心(CDC)视为对美国的紧急和严重的健康威胁。我们的长期目标是开发和评估肠杆菌科的新型抗生素。我们将通过纳米颗粒和树枝状铁载体塞来实现我们的目标。铁载体是由微生物合成并排泄出来的强大的铁络合剂，以隔离和返回它们生长所需的铁。所有肠杆菌科细菌都主要依靠铁载体肠杆菌素获取铁。由于铁是人体内细菌生长的限制因素(包括皮肤、血液、尿液和脑脊液中的铁)，这种铁载体长期以来一直被确定为所有肠杆菌科细菌的毒力因素。肠杆菌科的所有毒力菌株感染期间，肠杆菌素的外膜铁载体受体FepA的表达都多次被观察到增加。我们的中心假设是铁载体 阻断肠杆菌科铁载体运输系统的锚定将通过饥饿来显著降低细菌的毒力。本应用的总体目标是合成和评价一类新的肠杆菌素堵剂作为治疗肠杆菌科细菌的抗生素。这项拟议研究的基本原理是，需要更强大的抗生素和具有新作用模式的抗生素来治疗日益严重的疾病。 对当前药物有抗药性的流行细菌病原体。我们计划通过追求以下具体目标来实现我们的目标：1)合成阻断FepA受体的肠杆菌素塞子；2)评估肠杆菌素塞子作为抗生素的潜力。这项研究意义重大，因为它的目标是开发一种新型抗生素，这种抗生素利用一种新的 作用机制，并针对对当前几类抗生素具有抗药性的构成紧急和严重威胁的微生物。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抗生素的靶标，具有新的作用机制。参与铁摄取的转运体本身还没有被评估为抗生素的靶标。

 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.