Northern Antibiotics Ltd., Espoo, Finland.
Department of Bacteriology and Immunology, Helsinki University Medical School, Helsinki, Finland.
Med Res Rev. 2018 Sep;38(5):1661-1673. doi: 10.1002/med.21494. Epub 2018 Feb 27.
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.
黏菌素（多粘菌素 E）和多黏菌素 B 是杀菌性的五聚阳离子脂肽，特异性作用于革兰氏阴性菌，首先破坏其最外层的通透性屏障，即外膜（OM），然后破坏细胞质膜。多黏菌素 B 和黏菌素的发现均由三个实验室于 1947 年独立发表。随后，它们被用于静脉治疗。不幸的是，它们也表现出显著的、剂量限制的肾毒性。因此，黏菌素被保留为最后一线防御药物。现在，极其多药耐药株的出现迫使临床医生重新将黏菌素纳入严重感染的治疗方案中。然而，目前的剂量方案导致血清中的药物浓度不足，临床医生被建议使用更大剂量，这进一步增加了肾毒性的风险。最近，人们对开发更耐受和更有效的黏菌素的兴趣日益浓厚。这篇综述重点描述了四个开发项目，这些项目产生了新的衍生物，在动物感染模型中比旧的黏菌素更有效。来自三个项目的化合物在鲍曼不动杆菌和/或铜绿假单胞菌的啮齿动物肺感染模型中优于旧的黏菌素。其中一种在鲍曼不动杆菌小鼠大腿感染模型中也比多黏菌素 B 更有效。第四个项目包括在大肠杆菌小鼠肾盂肾炎中比多黏菌素 B 有效约 10 倍的化合物。
