Siderophore-based antibiotics: consequences for the microbiota and bacterial pathogens

项目摘要 这项研究的主要目的是使用铁载体抗生素结合物的基础上，天然的 铁载体平台将抗菌货物递送到革兰氏阴性细菌病原体和致病生物， 铁载体受体表达的基础和天然铁载体之间发生的分子识别， 铁载体及其受体。铁是几乎所有人类病原体和铁载体的必需营养素 是细菌产生的小分子铁螯合剂和毒力因子，用于获得这种必需的铁离子。 脊椎动物宿主体内的营养物质。我们假设，天然铁载体和 专用的铁载体受体允许铁载体附加的抗生素被导向选择的 细菌病原体，导致靶向抗生素递送。这种方法允许物种-和菌株- 基于铁载体受体选择病原体和致病生物的抗生素的特异性靶向 表情我们通过研究肠杆菌素和salmochelins，铁载体 由肠道革兰氏阴性菌产生，包括大肠杆菌和非伤寒沙门氏菌。在Aim中 1，我们将扩大我们的初步结果肠杆菌素和沙门氏菌螯铁蛋白介导的β- 内酰胺类抗生素氨苄西林（Ampicillin，Amx）对大肠杆菌周质的作用， 体外研究E.大肠杆菌和沙门氏菌，以解决摄取和抗菌机制，这些 化合物.在目标2中，我们将进行动物模型研究并确定是否施用本发明的化合物。 铁载体-β-内酰胺缀合物影响肠道微生物群的组成。而且还要 采用E.大肠杆菌和沙门氏菌的定植和感染来检验我们的假设， 施用我们的铁载体-β-内酰胺缀合物将更有选择性地靶向E.大肠杆菌和沙门氏菌， 在比母体β-内酰胺抗生素更低的剂量下有效。综合起来，这些结果 研究将为未来开发基于铁载体的工具提供基础， 操纵微生物群，以及治疗革兰氏菌引起的细菌感染的治疗方法， 负病原体利用这些有害生物所采用的铁获取系统， 在哺乳动物宿主中定居

PROJECT SUMMARY The primary objective of this research initiative is to use siderophore-antibiotic conjugates based on native siderophore platforms to deliver antibacterial cargo to Gram-negative bacterial pathogens and pathobionts on the basis of siderophore receptor expression and the molecular recognition that occurs between a native siderophore and its receptor(s). Iron is an essential nutrient for almost all human pathogens, and siderophores are small-molecule iron chelators and virulence factors produced by bacteria for acquiring this essential nutrient in the vertebrate host. We hypothesize that the exquisite interactions between native siderophores and dedicated siderophore receptors allow siderophore-appended antibiotics to be directed to select groups of bacterial pathogens, resulting in targeted antibiotic delivery. This approach allows for species- and strain- specific targeting of antibiotics to select pathogens and pathobionts on the basis of siderophore receptor expression. We address this hypothesis by investigating enterobactin and salmochelins, siderophores produced by enteric Gram-negative bacteria, including Escherichia coli and non-typhoidal Salmonella. In Aim 1, we will expand upon our preliminary results on enterobactin- and salmochelin-mediated delivery of the β- lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) to the periplasm of Escherichia coli and perform in vitro studies with E. coli and Salmonella to address the uptake and antibacterial mechanisms of these compounds. In Aim 2, we will perform animal model studies and determine whether administration of the siderophore-β-lactam conjugates affects the composition of the commensal microbiota. Moreover, we will employ animal models of E. coli and Salmonella colonization and infection to test our hypothesis that administration of our siderophore-β-lactam conjugates will more selectively target E. coli and Salmonella and be effective at lower doses than the parent β-lactam antibiotics. Taken together, the results from these investigations will provide the foundation for the future development of siderophore-based tools to study and manipulate the microbiota, as well as therapeutic approaches to treat bacterial infections caused by Gram- negative pathogens that harness the iron acquisition systems employed by these deleterious organisms when colonizing the mammalian host.