近日，丹麦奥胡斯大学Thomas B. Poulsen及其研究团队的最新研究通过多样性导向的半合成扩展了离子载体类抗生素的选择性。相关论文发表在2020年12月22日出版的《自然—化学》杂志上。

在该文中，研究人员展示了通过循环利用高丰度的聚醚组分，可高效构建结构新颖的聚醚类离子载体，从而获得与一系列天然聚醚离子载体相比抗菌选择性增强的类似物。研究人员对天然聚醚lasalocid和monensin使用经典的降解反应，并将其碎片化的产物与全合成提供的砌块结合，包括使用了卤化tetronic酸作为阳离子结合基团。这一研究表明对聚醚类离子载体进行结构优化是可能的，且这一领域代表着未来方法学创新的潜在机遇。

据悉，聚醚离子载体是一类可以使阳离子穿透生物膜的复杂天然产物。许多聚醚离子载体具有强大的抗微生物活性，并且一些化合物具有靶向侵袭性癌细胞的能力。然而，离子载体的功能被认为与其特异的细胞毒性有关，因此，尚未有对其进行人类临床开发的尝试。

附：英文原文

Title: Expanding the antibacterial selectivity of polyether ionophore antibiotics through diversity-focused semisynthesis

Author: Shaoquan Lin, Han Liu, Esben B. Svenningsen, Malene Wollesen, Kristian M. Jacobsen, Frederikke D. Andersen, Jaime Moyano-Villameriel, Christine N. Pedersen, Peter Nrby, Thomas Trring, Thomas B. Poulsen

Issue&Volume: 2020-12-22

Abstract: Polyether ionophores are complex natural products capable of transporting cations across biological membranes. Many polyether ionophores possess potent antimicrobial activity and a few selected compounds have the ability to target aggressive cancer cells. Nevertheless, ionophore function is believed to be associated with idiosyncratic cellular toxicity and, consequently, human clinical development has not been pursued. Here, we demonstrate that structurally novel polyether ionophores can be efficiently constructed by recycling components of highly abundant polyethers to afford analogues with enhanced antibacterial selectivity compared to a panel of natural polyether ionophores. We used classic degradation reactions of the natural polyethers lasalocid and monensin and combined the resulting fragments with building blocks provided by total synthesis, including halogen-functionalized tetronic acids as cation-binding groups. Our results suggest that structural optimization of polyether ionophores is possible and that this area represents a potential opportunity for future methodological innovation.

DOI: 10.1038/s41557-020-00601-1

Source: https://www.nature.com/articles/s41557-020-00601-1