Inhibition of the Essential TonB-ExbD Interaction in Escherichia coli

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 DESCRIPTION (provided by applicant): The outer membranes of Gram-negative bacteria are barriers to diffusion of certain nutrients into the periplasmic space and subsequent transport into the cell. To acquire large, scarce, important nutrients such as iron-siderophores and vitamin B12, active transporters with sub-nanomolar affinities for their transport substrates are located in the outer membrane. Because the outer membrane lacks a conventional energy source, energy for active transport of iron-siderophores and vitamin B12 across the outer membrane and into the periplasmic space derives from the protonmotive force of the cytoplasmic membrane. The TonB-ExbB-ExbD system in the cytoplasmic membrane appears to harvest protonmotive force and transduce it in an unknown form to the outer membrane active transporters. Our long-term goal is to understand the mechanism of TonB-dependent energy transduction between the cytoplasmic and outer membranes of Escherichia coli. Mutations in tonB render many pathogenic species significantly less fit. Due to the role that iron availability plays in infectious disease, it is widely recognized the TonB system has potential as a novel target for the development of new antibiotics. We now understand the interaction between TonB and ExbD sufficiently to identify agents which interrupt that interaction and could potentially serve as antibacterials or guide antibacterial development.