Biosynthesis and Secretion of Bacterial Siderophores

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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.