Siderophores are small-molecule metal-ion chelators biosynthesized and exported by various bacterial species during periods of nutrient deprivation for the acquisition of Fe(III). Siderophore-utilizing organisms express dedicated siderophore uptake machinery that allows for import of the iron-bound forms. The siderophore transport systems in Gram-negative bacteria therefore provide conduits across the outer membrane permeability barrier. We demonstrate that the enterobactin uptake machinery of Escherichia coli provides a means to deliver various small-molecule cargos across the outer membrane. Here we present the design and synthesis of monofunctionalized enterobactin platforms that provide site-specific handles for further synthetic elaboration, the assembly of enterobactin-cargo conjugates, and the evaluation of the requirements for cellular uptake and practical application. This work was supported by the PSWRCE (NIAID U54AI065359), the Searle Scholar Program, and the Department of Chemistry at  MIT.

Harnessing the iron acquisition machinery of gram-negative microbes for intracellular cargo delivery

247th National Meeting (2014)

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