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Expanding the antibacterial selectivity of polyether ionophore antibiotics through diversity-focused semisynthesis
Nature Chemistry ( IF 19.2 ) Pub Date : 2020-12-22 , DOI: 10.1038/s41557-020-00601-1
Shaoquan Lin 1 , Han Liu 1 , Esben B Svenningsen 1 , Malene Wollesen 1 , Kristian M Jacobsen 1 , Frederikke D Andersen 2 , Jaime Moyano-Villameriel 1 , Christine N Pedersen 1 , Peter Nørby 1 , Thomas Tørring 2 , Thomas B Poulsen 1
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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.



中文翻译:

通过聚焦多样性的半合成扩大聚醚离子载体抗生素的抗菌选择性

聚醚离子载体是能够跨生物膜运输阳离子的复杂天然产物。许多聚醚离子载体具有强大的抗菌活性,并且一些选定的化合物具有靶向侵袭性癌细胞的能力。然而,离子载体功能被认为与异质细胞毒性有关,因此,尚未进行人体临床开发。在这里,我们证明了结构新颖的聚醚离子载体可以通过回收高丰度聚醚的组分来有效地构建,以提供与一组天然聚醚离子载体相比具有增强的抗菌选择性的类似物。我们使用天然聚醚拉沙里菌素和莫能菌素的经典降解反应,并将所得片段与全合成提供的构件结合,包括卤素功能化的特酮酸作为阳离子结合基团。我们的结果表明,聚醚离子载体的结构优化是可能的,并且该领域代表了未来方法创新的潜在机会。

更新日期:2020-12-22
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