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

项目总结 这项研究的主要目标是使用铁载体-抗生素结合物基于天然的 铁载体平台向革兰氏阴性细菌病原体和病原体运送抗菌货物 铁载体受体表达和分子识别的基础 铁载体及其受体(S)。铁是几乎所有人类病原体和铁载体的必需营养素。 细菌产生的小分子铁络合剂和毒力因子是获得这种物质所必需的吗 脊椎动物宿主中的营养物质。我们假设本地铁载体和铁载体之间的精细相互作用 专用的铁载体受体允许附加铁载体的抗生素被定向到选定的 细菌病原体，导致有针对性的抗生素输送。这种方法允许物种-和品系- 根据铁载体受体特异性靶向选择病原体和病原体的抗生素 表情。我们通过研究肠动蛋白和鲑鱼藻蛋白，铁载体来解释这一假说。 由肠道革兰氏阴性细菌产生，包括大肠杆菌和非伤寒沙门氏菌。在AIM 1，我们将扩展我们关于肠杆菌素和沙莫胆碱介导的β-1传递的初步结果。 内酰胺类抗生素氨苄西林(Amp)和阿莫西林(AMX)对大肠杆菌周质的影响 对大肠杆菌和沙门氏菌的体外研究，以解决这些物质的摄取和抗菌机制 化合物。在目标2中，我们将进行动物模型研究，并确定给药是否 铁载体-β-内酰胺结合物影响共生微生物区系的组成。此外，我们还将 使用大肠杆菌和沙门氏菌定植和感染的动物模型来检验我们的假设 给药我们的铁载体-β-内酰胺结合物将更有选择性地针对大肠杆菌和沙门氏菌以及 在比母体β-内酰胺抗生素更低的剂量下有效。综上所述，这些结果 调查将为基于铁载体的工具的未来发展提供基础，以研究和 操纵微生物区系，以及治疗由革兰氏杆菌引起的细菌感染的方法 利用这些有害生物所使用的铁获取系统的负性病原体 在哺乳动物宿主上定居。

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.