Polymyxins are a class of lipopeptide anti-infective agents with potent and specific activity against Gram-negative bacteria. While toxicity concerns associated with polymyxin B and E (colistin) have historically limited their clinical application, today they are increasingly used as last-resort antibiotics given the rise of multidrug-resistant Gram-negative pathogens. The adverse side effects of polymyxins are well known, particularly as related to their nephrotoxicity. Here, we describe the synthesis and evaluation of a novel series of polymyxin analogues, aimed at reducing their nephrotoxic effects. Using a semisynthetic approach, we explored modifications of the exocyclic part of the polymyxin scaffold, namely, the terminal amino acid and lipophilic tail. By incorporating a reductively labile disulfide linkage in the lipid tail, we obtained novel polymyxins that exhibit potent antibacterial activity on par with polymyxin B but with reduced toxicity toward human renal proximal tubular epithelial cells.

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带有还原不稳定二硫化物连接脂质的多粘菌素的合成与评价

多粘菌素是一类脂肽抗感染剂，对革兰氏阴性菌具有强效和特异性活性。虽然与多粘菌素 B 和 E（粘菌素）相关的毒性问题历来限制了它们的临床应用，但如今，鉴于多重耐药性革兰氏阴性病原体的兴起，它们越来越多地被用作最后的抗生素。多粘菌素的不利副作用是众所周知的，特别是与它们的肾毒性有关。在这里，我们描述了一系列新的多粘菌素类似物的合成和评估，旨在减少它们的肾毒性作用。我们使用半合成方法探索了多粘菌素支架外环部分的修饰，即末端氨基酸和亲脂性尾部。通过在脂质尾部加入一个还原不稳定的二硫键，