Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.
J Med Chem. 2022 Dec 8;65(23):15878-15892. doi: 10.1021/acs.jmedchem.2c01528. Epub 2022 Nov 18.
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.
多黏菌素是一类脂肽类抗感染药物，对革兰氏阴性菌具有强大而特异的活性。虽然多黏菌素 B 和 E（黏菌素）的毒性问题一直限制了其临床应用，但随着抗药性革兰氏阴性病原体的出现，它们现在越来越多地被用作最后的抗生素。多黏菌素的不良反应是众所周知的，特别是与肾毒性有关。在这里，我们描述了一系列新型多黏菌素类似物的合成和评估，旨在降低其肾毒性。我们使用半合成方法探索了多黏菌素支架中环外部分，即末端氨基酸和疏水性尾部的修饰。通过在脂质尾部中引入可还原的二硫键，我们获得了新型多黏菌素，它们对人肾近端肾小管上皮细胞的毒性降低，但具有与多黏菌素 B 相当的强大的抗菌活性。
