Biosynthesis and Secretion of Bacterial Siderophores

细菌铁载体的生物合成和分泌

• 批准号: 341983-2012
• 负责人: Pawelek, Peter
• 金额: $ 2.04万
• 依托单位: Concordia University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=572435
• 关键词: Biosynthesis; Secretion; Bacterial; Siderophores

Protein-protein interactions are essential for many metabolic processes in living organisms, and thus key to survival. Iron is an essential nutrient for most bacteria, but this element is very scarce in the extracellular environment. In bacteria, protein interactions are required for iron uptake mechanisms necessary for survival in low-iron environments such as host serum. To obtain scarce yet essential iron, bacteria have developed an iron acquisition strategy that relies on molecules called siderophores. Bacteria synthesize siderophores in the cytoplasm and then secrete them in order to scavenge iron from their environment. It is known that a protein interaction network is required the biosynthesis of the E. coli siderophore enterobactin. E. coli cells that cannot synthesize enterobactin cannot grow in low-iron environments. We know very little about how biosynthetic proteins in the bacterial cytoplasm interact in order to synthesize siderophores and secrete them out of the cell. In pathogenic bacteria, the siderophore salmochelin is produced by adding sugars to enterobactin at specific positions. This glycosylated enterobactin evades the mammalian immune system and allows pathogens that synthesize salmochelin to survive in a host. We will study the protein interaction networks involved in the synthesis and secretion of enterobactin and salmochelin in order to gain fundamental knowledge that will help us to understand how pathogenic bacteria use siderophores as virulence factors. We will investigate how these proteins interact in our controlled laboratory environment by using biophysical techniques. We will also investigate these interactions as they occur in living cells. By combining our in vitro and in vivo approaches, we will better understand how to carry out targeted disruption of key protein interaction networks required for survival in pathogenic bacteria. Our research has potential applications in agriculture and the pharmaceutical industry in the development of novel antibiotics to protect poultry, livestock, and humans, against bacterial infections.

蛋白质之间的相互作用对生物体的许多代谢过程都是必不可少的，因此也是生存的关键。铁是大多数细菌的必需营养素，但在细胞外环境中，这种元素非常稀缺。在细菌中，蛋白质相互作用是在低铁环境中生存所必需的铁摄取机制所必需的，例如宿主血清。为了获得稀缺但必不可少的铁，细菌开发了一种铁获取策略，这种策略依赖于被称为铁载体的分子。细菌在细胞质中合成铁载体，然后分泌它们，以便从环境中清除铁。众所周知，大肠杆菌铁载体Enterobactin的生物合成需要一个蛋白质相互作用网络。不能合成肠杆菌素的大肠杆菌细胞不能在低铁环境中生长。我们对细菌细胞质中的生物合成蛋白如何相互作用以合成铁载体并将其分泌出细胞知之甚少。在病原菌中，铁载体沙莫胆碱是通过在特定位置将糖添加到肠杆菌蛋白中而产生的。这种糖基化的肠杆菌素可以躲避哺乳动物的免疫系统，并允许合成沙莫胆素的病原体在宿主体内存活。我们将研究肠杆菌素和Salmochelin合成和分泌过程中涉及的蛋白质相互作用网络，以获得有助于我们理解病原菌如何利用铁载体作为毒力因子的基础知识。我们将使用生物物理技术研究这些蛋白质如何在我们受控的实验室环境中相互作用。我们还将研究在活细胞中发生的这些相互作用。通过结合我们的体外和体内方法，我们将更好地了解如何有针对性地破坏病原菌生存所需的关键蛋白质相互作用网络。我们的研究在农业和制药业开发新型抗生素以保护家禽、牲畜和人类免受细菌感染方面具有潜在的应用价值。