Thiosquaramides: dual-function ionophores for Zn2+ and Cl− with ion dependent anti-microbial activity

Abstract

Synthetic transmembrane transporters have garnered considerable interest in medicinal chemistry for their ability to modulate cellular processes via ion transport. These ionophores can disrupt intracellular ion homeostasis, often triggering biological responses such as programmed cell death or antimicrobial effects. In this study, we present a series of thionated squaramides that demonstrate dual binding affinity for both metal cations and anionic species, as confirmed by spectroscopic analyses and single-crystal X-ray crystallography. While thiosquaramides have previously been shown to mediate chloride transport across lipid bilayers, we now report their capacity to facilitate Zn²⁺ transport, as assessed using the FluoZin-3 fluorescence assay in a vesicle model. Notably, the ability of these thiosquaramides to act as zinc ionophores correlates with a distinct Zn²⁺-dependent antimicrobial response against Staphylococcus aureus. These findings establish a clear link between zinc transport and biological activity, suggesting that thiosquaramides function through a novel ionophoric mode of action. Collectively, this work introduces a new class of dual-function ionophores with potential as antimicrobial agents and underscores the value of structural diversification in the design of supramolecular therapeutics.