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.