Synthesis of staphyloferrin B (SB)-cargo conjugates

Abstract

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 siderophore-mediated 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.