A vital part of the human innate immune response involves iron-withholding at sites of infection. This defense mechanism limits the availability of this essential nutrient to invading pathogens. To acquire iron from the limited host environment, many bacteria produce and utilize siderophores, a family of small-molecule high-affinity iron chelators. One of the two siderophores produced by Staphylococcus aureus is named staphyloferrin B. Staphyloferrin B is a polycarboxylate siderophore which is produced in vivo by NRPS-independent siderophore synthetases and is composed of the building blocks: L-2,3-diaminopropionic acid, citric acid, and α-ketoglutaric acid. Studies suggest that staphyloferrin B is a virulence factor of S. aureus and this siderophore is therefore a potential target for treatment of MRSA infections.[1] Staphyloferrin B was previously prepared in vitro by using the biosynthetic machinery;[2] however, to date no total synthesis of this siderophore has been reported. In this study, we present the first total synthesis of staphyloferrin B and analogs thereof. The array of molecules was employed in investigations of iron-chelation and structure activity relationship in order to probe the requirements for staphyloferrin B-mediated iron acquisition in S. aureus. Access to staphyloferrin B through the presented total synthesis allows for further investigations of the role of this siderophore as a virulence factor and its potential as an antibiotic target. [1] Lindsay, J. A.; Riley, T. V.; Mee, B. J. Eur. J. Clin. Microbiol. Infect. Dis. 1994, 13, 1063. [2] Cheung, J.; Beasley, F. C.; Liu, S.; Lajoie, G. A.; Heinrichs, D. E. Mol. Microbiol. 2009, 74, 594.

Staphyloferrin B: Total synthesis, structure activity relationship studies, and bioactivity

249th National Meeting (2015)

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