Polymyxin B and colistin (polymyxin E) are bactericidal pentacationic lipopeptides that act specifically on Gram‐negative bacteria, first by disrupting their outermost permeability barrier, the outer membrane (OM), and then damaging the cytoplasmic membrane. The discovery of both polymyxin B and colistin was published independently by three laboratories as early as in 1947. They were subsequently used in intravenous therapy. Unfortunately, they also exhibit significant and dose‐limiting nephrotoxicity. Therefore, polymyxins were reserved as agents of last‐line defense. The emergence of extremely multiresistant strains has now forced clinicians to reinstate polymyxins in the therapy of severe infections. However, the current dosage regimens lead to insufficient drug concentrations in serum and clinicians have been advised to use larger doses, which further increases the risk of nephrotoxicity. Very recently, the interest in developing better tolerated and more effective polymyxins has grown. This review focuses on describing four development programs that have yielded novel derivatives that are more effective than the old polymyxins in animal infection models. Compounds from three programs are superior to the old polymyxins in the rodent lung infection model with Acinetobacter baumannii and/or Pseudomonas aeruginosa. One of them is also more effective than polymyxin B in A. baumannii mouse thigh infection. The fourth program includes compounds that are approximately tenfold more effective in Escherichia coli murine pyelonephritis than polymyxin B.

中文翻译：

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与多粘菌素B和粘菌素相比，新的多粘菌素衍生物在动物感染模型中显示出更高的功效

多粘菌素B和粘菌素（polymyxin E）是杀菌性的五种阳离子脂肽，它们首先对革兰氏阴性细菌起作用，首先破坏它们的最外层通透性屏障即外膜（OM），然后破坏细胞质膜。早在1947年，三个实验室就独立发表了多粘菌素B和粘菌素的发现。它们随后被用于静脉治疗。不幸的是，它们还表现出明显的剂量限制性肾毒性。因此，多粘菌素被保留为最后一道防线。现在，极具多重耐药性的菌株的出现已迫使临床医生在严重感染的治疗中恢复多粘菌素。但是，当前的剂量方案会导致血清中药物浓度不足，建议临床医生使用更大剂量的药物，这进一步增加了肾毒性的风险。最近，人们对开发更好的耐受性和更有效的多粘菌素的兴趣不断增长。这篇综述的重点是描述四个开发程序，这些程序在动物感染模型中产生了比旧的多粘菌素更有效的新衍生物。在啮齿动物的肺部感染模型中，来自三个程序的化合物优于旧的多粘菌素鲍曼不动杆菌和/或铜绿假单胞菌。其中之一在鲍曼不动杆菌小鼠大腿感染中也比多粘菌素B更有效。第四个程序包括在大肠杆菌鼠类肾盂肾炎中比多粘菌素B有效约十倍的化合物。