Synthesis of Staphyloferrin B ( SB ) - Cargo Conjugates

The ability of the Gram-positive human pathogen Staphylococcus aureus to cause infection and develop antimicrobial resistance poses a significant threat to public health. One potential method to combat bacterial infections involves the use of siderophore-drug conjugates to selectively deliver antibiotics to bacteria. Siderophores are low-molecular-weight chelators with high affinity for iron(Ill) that are biosynthesized by bacteria to acquire iron from the environment. Several reports of siderophoremediated delivery of antibiotics to Gram-negative bacteria have been published. However, only a few examples of applying this strategy to Gram-positive bacteria are reported. Here, the potential of staphyloferrin B (SB), a polycarboxylate siderophore and virulence factor biosynthesized by S. aureus, for siderophore-drug conjugates is considered. In this thesis, the design and synthesis of a monofunctionalized SB scaffold in which the siderophore is site-electively modified with a polyethyleneglycol (PEG 3) linker and an azide moiety as a chemical handle is presented. The total synthesis of the monofunctionalized SB scaffold in 17 steps starting from 5 commercially available starting materials is reported. This molecule was employed to prepare a family of three SB-cargo conjugates using copper-catalyzed Click chemistry. In future work, these molecules can be used to probe the extent to which the S. aureus ferric-SB uptake and processing machinery recognizes, transports, and utilizes the derivatized SB scaffolds. Moreover, different antibiotics can be conjugated to SB and the effect on antimicrobial activity can be assessed. Thesis Supervisor: Elizabeth M. Nolan Title: Associate Professor of Chemistry