Rational Design of Silicon-Based Zinc Ionophores.

Ionophores transport ions across biological membranes and have wide-ranging applications, but a platform for their rapid development does not exist. We report a platform for developing ionophores from metal-ion chelators, which are readily available with wide-ranging affinities and specificities, and structural data that can aid rational design. Specifically, we fine-tuned the binding affinity and lipophilicity of a Zn II -chelating ligand by introducing silyl groups proximal to the Zn II -binding pocket, which generated ionophores that performed better than most of the currently known Zn II ionophores. Furthermore, these silicon-based ionophores were specific for Zn II over other metals and exhibited better antibacterial activity and less toxicity to mammalian cells than several known Zn II ionophores, including pyrithione. These studies establish rational design principles for the rapid development of potent and specific ionophores and a new class of antibacterial agents.