期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 61, 期 23, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202201698
关键词
Antibacterial Activity; Ionophores; Pyrithione; Silyl Groups; Zinc Ions
资金
- Burroughs Wellcome Fund (Career Award at the Scientific Interface)
- NIH [R21AI162662, UC4DK116255, R01 DK113597]
- Ajinomoto Co., Inc.
We report a platform for the rapid development of ionophores using metal-ion chelators. The improved ionophores showed better specificity and performance for Zn-II, as well as superior antibacterial activity and lower toxicity to mammalian cells.
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.
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