Golbek Thaddeus W, Schmüser Lars, Rasmussen Mette H, Poulsen Thomas B, Weidner Tobias
Department of Chemistry, Aarhus University, 8000 Aarhus, Denmark.
Langmuir. 2020 Mar 31;36(12):3184-3192. doi: 10.1021/acs.langmuir.9b03752. Epub 2020 Mar 20.
Carboxyl polyether ionophores (CPIs) are widely used as veterinary antibiotics and to increase food utilization in ruminating animals. Furthermore, CPIs can target drug-resistant bacteria, but detailed knowledge about their mode-of-action is needed to develop agents with a reasonable therapeutic index. It has been suggested that ionophores bind to membranes and incur large structural changes to shield a bound ion from the hydrophobic environment of the lipid bilayer for transport. One crucial piece of information is missing, however: Is it necessary for the free ionophore to adsorb on the membrane surface before interacting with a cation to facilitate cross-membrane ion transport? To answer this question, we applied sum-frequency generation (SFG) vibrational spectroscopy and surface tensiometry to identify the interaction between the prototypical CPI lasalocid acid (LA) and a model membrane. Observed changes in the surface pressure demonstrate that the free LA undergoes a self-assembly process with the lipid monolayer. Spectra taken from the lipid monolayer show that the free acid inserts partially into the lipid monolayer and then after complexation with sodium chloride disrupts the lipid monolayer. Overall, this study strongly suggests that this must be the crucial step of LA and metal ion complexation that allows the ionophore to traverse a lipid membrane.
羧基聚醚离子载体（CPIs）被广泛用作兽用抗生素，并用于提高反刍动物的食物利用率。此外，CPIs可以靶向耐药细菌，但需要详细了解其作用模式，以开发具有合理治疗指数的药物。有人提出，离子载体与膜结合，并发生大的结构变化，以保护结合的离子免受脂质双层疏水环境的影响，从而实现运输。然而，缺少一个关键信息：游离离子载体在与阳离子相互作用以促进跨膜离子运输之前，是否有必要吸附在膜表面？为了回答这个问题，我们应用和频振动光谱（SFG）和表面张力测定法来确定典型的CPl拉沙洛西酸（LA）与模型膜之间的相互作用。观察到的表面压力变化表明，游离的LA与脂质单层发生自组装过程。从脂质单层获得的光谱表明，游离酸部分插入脂质单层，然后在与氯化钠络合后破坏脂质单层。总体而言，这项研究强烈表明，这必定是LA与金属离子络合的关键步骤，该步骤使得离子载体能够穿过脂质膜。
