Biosynthesis and Secretion of Bacterial Siderophores

蛋白质之间的相互作用对生物体的许多代谢过程至关重要，因此对生存至关重要。铁是大多数细菌必需的营养物质，但这种元素在细胞外环境中非常稀缺。在细菌中，蛋白质相互作用是在低铁环境（如宿主血清）中生存所必需的铁摄取机制。为了获得稀缺但必需的铁，细菌已经开发出一种依赖于称为铁载体的分子的铁获取策略。细菌在细胞质中合成铁载体，然后分泌铁载体，从环境中清除铁。众所周知，大肠杆菌铁载体肠杆菌的生物合成需要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。在致病菌中，铁载体盐切碱是通过在肠杆菌蛋白的特定位置添加糖而产生的。这种糖基化的肠杆菌素避开了哺乳动物的免疫系统，并允许合成肠杆菌素的病原体在宿主体内存活。我们将研究肠obactin和salmochelin合成和分泌中的蛋白质相互作用网络，以获得有助于我们了解致病菌如何利用铁载体作为毒力因子的基础知识。我们将通过使用生物物理技术来研究这些蛋白质如何在我们控制的实验室环境中相互作用。我们还将研究这些相互作用，因为它们发生在活细胞中。通过结合我们的体外和体内方法，我们将更好地了解如何对致病菌存活所需的关键蛋白质相互作用网络进行靶向破坏。我们的研究在农业和制药工业中有潜在的应用，可以开发新的抗生素来保护家禽、牲畜和人类免受细菌感染。

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.